Biochimica et Biophysica Acta 1793 (2009) 697–709
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Biochimica et Biophysica Acta
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / b b a m c r
Review
Neuronal ceroid lipofuscinoses
Anu Jalanko a,⁎, Thomas Braulke b
a
b
National Public Health Institute, Department of Molecular Medicine and FIMM, Institute for Molecular Medicine Finland, Biomedicum, PO 104, 00251 Helsinki, Finland
Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
a r t i c l e
i n f o
Article history:
Received 11 August 2008
Received in revised form 6 November 2008
Accepted 12 November 2008
Available online 24 November 2008
Keywords:
NCL
Lysosome
Neurodegeneration
Lysosomal storage disease
Animal model
a b s t r a c t
The neuronal ceroid lipofuscinoses (NCL) are severe neurodegenerative lysosomal storage disorders of
childhood, characterized by accumulation of autofluorescent ceroid lipopigments in most cells. NCLs are
caused by mutations in at least ten recessively inherited human genes, eight of which have been
characterized. The NCL genes encode soluble and transmembrane proteins, localized to the endoplasmic
reticulum (ER) or the endosomal/lysosomal organelles. The precise function of most of the NCL proteins has
remained elusive, although they are anticipated to carry pivotal roles in the central nervous system. Common
clinical features in NCL, including retinopathy, motor abnormalities, epilepsia and dementia, also suggest that
the proteins may be functionally linked. All subtypes of NCLs present with selective neurodegeneration in the
cerebral and cerebellar cortices. Animal models have provided valuable data about the pathological
characteristics of NCL and revealed that early glial activation precedes neuron loss in the thalamocortical
system. The mouse models have also been efficiently utilized for the evaluation of therapeutic strategies. The
tools generated by the accomplishments in genomics have further substantiated global analyses and these
have initially provided new insights into the NCL field. This review summarizes the current knowledge of the
NCL proteins, basic characteristics of each disease and studies of pathogenetic mechanisms in animal models
of these diseases.
© 2008 Elsevier B.V. All rights reserved.
1. Introduction
The neuronal ceroid lipofuscinoses (NCLs) comprise a group of most
common inherited, progressive neurodegenerative diseases of childhood
[1]. The incidence (affected persons per live newborns) in USA and
Scandinavian countries is 1:12 500 while the world-wide incidence is
1:100 000 [2]. To date approximately 160 NCL causing mutations have
been found in eight human genes (CLN1, CLN2, CLN3, CLN5, CLN6, CLN7,
CLN8 and CLN10, http://www.ucl.ac.uk/ncl) [3–6] (Table 1). Additionally, mutations in the CLCN7 gene cause osteopetrosis and an NCL-like
disorder [7]. Despite being a genetically heterogeneous group, the NCLs
share histopathological and clinical characteristics. Two most essential
findings in all NCLs include degeneration of nerve cells mainly in the
cerebral and cerebellar cortices and accumulation of autofluorescent
ceroid lipopigments, in both neural and peripheral tissues. Typical clinical
findings include retinopathy leading to blindness, sleep problems, motor
abnormalities, epilepsia, dementia and eventually premature death
[1,8,9]. The NCLs were originally classified based on the clinical onset of
symptoms to four main forms: infantile (INCL), late-infantile (LINCL),
juvenile (JNCL) and adult (ANCL). The CLN1, CLN5, CLN6 and CLN7
diseases were originally identified in limited populations but more
Abbreviations: GROD, granular osmiophilic deposits; CLP, curvilinear profiles; ER,
endoplasmic reticulum; FPP, fingerprint profiles; RLP, rectilinear profiles
⁎ Corresponding author. Tel.: +358 9 4744 8392; fax: +358 9 4744 8480.
E-mail addresses: Anu.Jalanko@ktl.fi (A. Jalanko), [email protected]
(T. Braulke).
0167-4889/$ – see front matter © 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbamcr.2008.11.004
recently mutations have been found in many other countries. Also several
variant forms have been recognised having later onset than the classical
forms or being less severe or protracted in course [10,11] (Table 1).
NCLs are considered as lysosomal storage diseases (LSDs), however,
also many distinct characteristics are observed. In NCLs the ceroid
lipopigments are accumulated in the lysosomes and many of the NCL
proteins are present in the lysosomes, both characteristics of LSDs
[12,13]. In classical LSDs, the deficiency/dysfunction of an enzyme or
transporter leads to accumulation of specific undegraded substrates or
metabolites, respectively, in lysosomes (see articles by V. Gieselmann
and Ballabio, and by R. Ruivo et al. in this issue). However, the
accumulating material in NCLs is not a disease specific substrate and
the main storage material is the subunit c of mitochondrial ATP
synthase or sphingolipid activator proteins A and D [14,15]. The precise
function of the NCL proteins as well as the disease mechanisms is
largely unknown. The advancement in cell biological and genome-wide
analyses [13,16] as well as development of various model organisms
[17,18] has produced a vast amount of data for NCL biology and these
achievements are summarized in this review.
2. CLN1
2.1. CLN1 gene and protein
The CLN1 gene resides on chromosome 1p32 and encodes palmitoyl
protein thioesterase 1 (PPT1) [19]. PPT is a well-characterized enzyme
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that cleaves palmitate from H-Ras in vitro [20]. The 306 amino acid
PPT1 polypeptide contains a 25 amino acid N-terminal signal sequence
that is cotranslationally cleaved. PPT1 migrates as a 37/35-kDa doublet
and has three N-linked glycosylation sites at amino acid positions 197,
212 and 232, all of them utilized in cells upon overexpression.
Glycosylation is required for stability and activity of the enzyme
[21,22]. The crystal structure of bovine PPT1 (95% identical residues
compared with human PPT1) reveals an α/β-serine hydrolase
structure, typical of lipases, with a catalytic triad composed of
Ser115–His289–Asp233. Overexpressed PPT1 is routed to late-endosomes/lysosomes via the mannose 6-phosphate receptor (M6PR)mediated pathway in non-neuronal cells [21,23, Fig. 1]. Utilization of
the M6PR pathway has not been experimentally characterized in
neurons but PPT1 is present in the human brain mannose 6phosphoproteome [24]. Although Ppt1 is localized in lysosomes in
mouse neurons [25], in brain tissue as well as in cultured neurons
Ppt1/PPT1 has been detected in the cell soma, axonal varicosities and
presynaptic terminals, including synaptosomes and synaptic vesicles
[26–30]. Analysis of glycosylation, transport and complex formation of
PPT1 has further implicated distinct characteristics in neurons [31].
Due to the capability to cleave palmitate residues PPT1 is expected to
function near cell membranes and overexpressed PPT1 has been found
to partly associate with lipid rafts [32].
In neurons, palmitoylation targets proteins for transport to nerve
terminals and regulates trafficking at synapses [33]. The exact
physiological function and in vivo substrates of PPT1 still remain elusive,
but it is proposed that PPT1 participates in various cellular processes,
including apoptosis, endocytosis, vesicular trafficking, synaptic function
Table 1
Classification of the NCLs
Gene
Disease
Protein
Main
Storage
storage
ultrastructurea material
CLN1
Infantile, also late
infantile, juvenile
and adult
Late infantile,
juvenile
PPT1, palmitoyl protein
thioesterase, lysosomal
enzyme
TPP1, tripeptidyl
peptidase 1, lysosomal
enzyme
CLN3, lysosomal
transmembrane protein
GROD
CLN2
CLP
CLN3
Juvenile
FPP
CLN4b
Adult
Not known
FPP,
granular
CLN5
Late infantile,
Finnish variant
CLN5, soluble lysosomal
protein
RLP, CLP,
FPP
CLN6
Late infantile
CLN6, transmembrane
protein of ER
RLP, CLP,
FPP
CLN7
(MFSD8)
Late infantile,
Turkish variant
CLN8
Late infantile,
Northern epilepsy
MFS8, lysosomal
RLP, CLP,
transmembrane protein of FPP
MFS facilitator family
CLN8, transmembrane
CLP
protein of ER
CLN9 (not
Juvenile
identified)
Not known
CLP (FPP,
GROD)
CLN10
(CTSD)
Congenital, late
infantile
GROD
CLCN7
Infantile
osteopetrosis and
CNS degeneration
CTSD, cathepsin D,
lysosomal protein with
multiple functions
CLC7, lysosomal chloride
channel/exchanger
Not
known
Saposins
A and D
Subunit c
of ATP
synthase
Subunit c
of ATP
synthase
Subunit c
of ATP
synthase
Subunit c
of ATP
synthase
Subunit c
of ATP
synthase
Subunit c
of ATP
synthase
Subunit c
of ATP
synthase
Subunit c
of ATP
synthase
Saposins
A and D
Subunit c
of ATP
synthase
Disease phenotypes, affected proteins, storage ultrastructure and the main storage
materials.
a
See “Abbreviations”.
b
CLN4 disease is very rare and not discussed in this chapter.
and lipid metabolism. PPT1 might be involved in cell death signaling,
because overexpression of PPT1 protects cells against induced apoptosis
[34] and reduced expression of PPT1 increases the susceptibility to
induced apoptosis [35]. Under basal conditions, PPT1 deficient lymphoblasts are more sensitive to apoptosis [36]. PPT1 deficiency in INCL
patient fibroblasts results in elevation of lysosomal pH and defects in
endocytosis [37,38]. Recent observations have linked PPT1 to lipid
metabolism as it was found to interact with the ectopic F1-ATP-synthase
and to modulate ApoA1 uptake in neurons [39].
2.2. CLN1 disease
Infantile neuronal ceroid lipofuscinosis (INCL, MIM#256730) is
caused by mutations in the CLN1 gene. To date, 45 disease causing
mutations have been described in the CLN1 (http://www.ucl.ac.uk/
ncl/). The CLN1 mutations are distributed throughout the gene and
most of them affect only individual families. The Finnish population
forms an exception as in most families a missense mutation
(c.364A NT, Arg122Trp) is found. Most of the reported mutations
cause a severe early onset INCL phenotype, although mutations
causing late infantile, juvenile and even adult phenotypes have also
been characterized [9,40–42]. However, no clear phenotype–genotype
correlation has been described, possibly indicating other underlying
factors such as modifier genes since the mutations lead to severe loss
of PPT1 enzymatic activity. The infantile CLN1 disease manifests
during the second half of the first year of life and is characterized by
visual failure, microcephaly, seizures, mental and motor deterioration
leading to vegetative stage and most children with INCL die around
10 years of age [2]. Most cell types of INCL patients accumulate
autofluorescent lysosomal storage deposits, called granular osmiophilic deposits (GRODs). The major part of the GRODs consists of
sphingolipid activator proteins, saposins A and D. Even though
accumulation of various saposins has been reported in lysosomal
storage diseases, INCL is typified by massive accumulation and
abnormal processing of saposins A and D [14,38].
2.3. Cln1 animal models
Two mouse models for INCL have been generated by different
targeting strategies, including deletion of Ppt1 exon 9 (Cln1−/−) or exon
4 (Ppt1Δex4) [43,44, Table 2]. Both of the mouse models exhibit a severe
INCL phenotype and display widespread inflammation-mediated
neurodegeneration late in the course of the disease [44], but this is
remarkably selective earlier in pathogenesis with localized astrocytosis
and neuronal loss in the thalamocortical system [45,46]. Transcript
profiling of young Cln1−/− and Ppt1Δex4mice [47,48], suggest dysregulation of lipid metabolism, trafficking, glial activation, calcium homeostasis and neuronal development, most of which have been connected
to the pathogenesis of human INCL [8,16,49–51]. Although the cell
biological analyses would highlight a link of Ppt1 with synaptic
functions, data arising from neuron cultures or acute brain slices reveal
no alterations in synaptic transmission. Only the number of readily
releasable pool of synaptic vesicles is reduced [25,52]. Ppt1 deficiency in
neurons has also been linked to ER-mediated cellular stress [53]. Gene
expression profiling and biochemical analyses in developing Ppt1
deficient neurons further highlighted an increase in cholesterol
biosynthesis and defective ApoAI metabolism [39,52]. A role of INCL
in lipid metabolism has been implicated also by previous studies
analyzing lipid composition in human autopsy material [51,54,55]. The
landmarks of the pathology of the NCL mouse models are summarized
in Table 2 and additional information is available in the NCL mouse
model database (http://www.ucl.ac.uk/ncl/mouse.shtml). The Cln1
deficient mouse model has been utilized for therapeutic trials and
amelioration of functional deficits has been reported [56,57].
The generation of other, small eukaryotic model systems or small
vertebrate models will be crucial for the understanding of the NCL
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699
Table 2
Mouse models of NCLs
Gene/mutation
Phenotype
Neuropathology
Neuronal function/other characteristics
Storage
Cln1
Cln1−/−:
del ex 9
Ppt1 Δex4: del ex 4
Cln2
Neoins
Arg446His
Cln3
Cln3−/−:
del ex 1–6
Cln3 Δex7–8
Cln3 KO:
del ex 7–8
Cln3 KI reporter:
del ex 1–8, ins β-gal
Cln5
del ex 3
Cln6
nclf
c.307insC
Cln8
mnd
c.267–268insC
Ctsd
Del ex 4
Loss of vision at 3–4 months;
motor abnormalities, seizures,
shortened life span
Thalamocortical atrophy,
progressive glial activation
Normal electrophysiology, synaptic abnormalities, slight
changes in Ca, early changes in neuronal cholesterol
biosynthesis
GROD,
autofluorescence
Constant tremor, motor
abnormalities, ataxia, markedly
shortened life span
Shortened life spans in other
models than Cln3−/−
Thalamocortical and cerebellar
atrophy, progressive glial activation
Not analyzed
Subunit c of ATP
synthase, CLP
autofluorescence
Subunit c of ATP
synthase, FPP,
autofluorescence
Clcn7
del ex 3–7
Loss of vision at 5 months,
shortened life span
Motor dysfunctions, spastic
limb paresis, shortened life
span
Severe paralysis, shortened life
span
Late-onset thalamocortical atrophy, Vulnerability to glutamate receptor overactivation, mild
early low level glial activation, optic mitochondrial, synaptic and cytoskeletal abnormalities,
nerve degeneration
autoimmune response, autophagy
Unpublished
Abnormalities of cytoskeleton, myelinization and RNA
processing in gene expression profiling
Accumulation of GM2 and GM3, reduced expression of
GABAA2
Retinal atrophy
CLP, FPP,
autofluorescence
RLP, CLP, FPP,
autofluorescence
Retinal atrophy
Changes in lipid metabolism, alterations in glutamatergic CLP, autofluorescence
neurotransmission
Severe seizures, blindness,
anorexia, death at 26 days
Thalamocortical atrophy and glial
activation, axonal degeneration
Impaired GABAergic neurotransmission, acc. of GM2 and
GM3, abnormal lysophospholipid, apoptotic cell death
Severe osteopetrosis, death
within 7 weeks
Retinal degeneration, degeneration
of CA3 pyramidal cells, microglial
activation
Antigen presentation, complement components and
microglial activation in gene expression profiling
biology. To date, nematode and Drosophila models exist for CLN1
disease but so far have produced limited amount of data. The C.
elegans ppt1-mutants do not display the hallmarks of NCL pathology,
but interestingly, these worms exhibit mitochondrial abnormalities
[58]. Ppt1−/− flies accumulate storage material but do not develop
neurodegeneration [59], possibly reflecting differences in the lipid
metabolism between mammals and flies.
Subunit c of ATP
synthase GROD,
autofluorescence
Subunit c of ATP
synthase, GROD, FPP,
autofluorescence
The crystal structure of TPP1 has not been established, but homology
and mutational analyses have identified Ser475 as the active site
nucleophile, and Glu272 and Asp276 to be involved in the catalytic
reaction [69,70]. In vivo substrates for TPP1 are not known whereas
subunit c can be processed by TPP1 in vitro [71]. Other potential
substrates include β-amyloid peptide [72], angiotensins I and II,
glucagons, cholecystokinin and neuromedin [61,73] but none of these
are included in the storage material.
3. CLN2
3.2. CLN2 disease
3.1. CLN2 gene and protein
The CLN2 gene on chromosome 11p15 encodes the CLN2 protein
tripeptidyl peptidase 1 [60]. Increased TPP1 protein amounts have been
described in various pathological conditions such as neurodegenerative
lysosomal storage disorders, inflammation, cancer and aging [61]. TPP1
activity is significantly elevated in CLN3 disease (juvenile NCL, JNCL) and
the proteins have been reported to interact, but the physiological
relevance of the interaction remained elusive [62,63]. TPP1 is a lysosomal
hydrolase that removes tripeptides from the N-terminus of small
polypeptides [61, Fig. 1]. The TPP1 polypeptide contains 563 amino
acids and is synthesized as an inactive precursor with 19 amino acid
signal peptide that is cotranslationally cleaved in the ER lumen. The
proenzyme contains a 176 amino acid prosegment that is autocatalytically cleaved upon entry into lysosomes. The mature enzyme consists of a
368 amino acids comprising the catalytic domain [64,65]. TPP1 contains
five used N-glycosylation sites of high mannose and complex type
oligosaccharides. Proper N-glycosylation is essential for the maturation
and lysosomal targeting of TPP1 [66]. Interestingly, TPP1 protein was
originally identified as an abundant 46 kDa mannose 6-phosphorylated
protein that was absent in the brain specimens from late infantile NCL
(LINCL) patients [60]. Endogenous TPP1 is efficiently transported to
lysosomes in an M6PR-dependent manner also in neurons [67].
TPP1 is the only known mammalian representative of pepstatin Ainsensitive serine carboxyl proteases, also known as sedolisins [68].
Mutations in the CLN2 gene lead to classic late infantile neuronal
ceroid lipofuscinosis or Jansky–Bielschowsky disease (LINCL, MIM
#204500) and to date, 56 disease-causing mutations have been
described (http://www.ucl.ac.uk/ncl/). All mutations result in loss or
marked deficiency of the TPP1 activity and usually in the absence of
the protein [74]. The two most common mutations are the splice site
mutation IV5-1G N C and the nonsense mutation Arg208X resulting in
broadly similar clinical phenotypes [11]. LINCL has an onset of 2–
4 years [75]. Seizures and ataxia predominate the early clinical course,
followed by progressive cognitive and motor dysfunction. Visual
impairment develops later in the course of the disease. The
ultrastructural findings include curvilinear profiles (CLP) found in
lysosomal residual bodies, being the hallmark of CLN2 disease. LINCL
is accompanied by prominent and widespread neuronal loss especially in the cerebellum and CAII region of the hippocampus. The
storage bodies contain subunit c of mitochondrial ATP synthase and
low amounts of saposins A and D. The subunit c comprises of 85% of
the protein content of the storage material [76].
3.3. CLN2 animal models
The CLN2 protein is not very well conserved among small eukaryotic organisms and to date the Cln2−/− mouse model [77, Table 2]
and a recently characterized naturally occurring dog model [78]
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represent the only animal models for CLN2 disease. The Tpp1
enzyme activity is abolished in the mouse model. The mice present
with a rapid neurodegenerative phenotype and show an accumulation of storage material with ultrastructure of curvilinear profiles,
typical for LINCL. Neuropathologically this mouse shows pronounced degeneration within the thalamocortical system and
cerebellar atrophy [77]. Recently, relevant neuropathological and
behavioural hallmarks of disease were characterized in this mouse
model and were correlated with tissues from LINCL patients.
Progressive reactive astrocytosis was observed in the motor cortex,
hippocampus, striatum and cerebellum [67]. The CLN2 mouse model
has been utilized for therapeutic trials. Cln2−/− mice treated with
enzyme replacement therapy or adeno-associated virus (AAV)mediated gene therapy have shown attenuated neuropathology
[67,79–81]. Currently, human vLINCL patients are undergoing the
first AAV-mediated therapeutic trials [82]. The canine model shows
typical ultrastructure associated with CLN2 disease but to date the
neuropathology has not been thoroughly assessed [78].
4. CLN3
4.1. CLN3 gene and protein
The CLN3 gene on chromosome 16p12 encodes a hydrophobic
integral membrane protein of 438 amino acids [83]. CLN3 possesses
six transmembrane domains and both N- and C-termini face the
cytoplasm [84–87]. CLN3 utilizes two N-glycosylation sites, at Asn71
and Asn85 and the glycosylation varies in different tissues [84,86].
Overexpressed CLN3 protein is localized into lysosomes in non-neuronal cells [88, Fig. 1]. In neurons, CLN3 is detected in the endosomal/
lysosomal structures and gets transported to synaptosomes
[85,86,89]. Some studies have detected small portions of the CLN3
protein at the plasma membrane and also in membrane lipid raft
preparation [86,90–92]. CLN3 contains two lysosomal targeting
motifs. The first comprises a dileucine motif, Leu253Ile254, with an
upstream acidic patch [85,93]. Controversial data exists whether CLN3
binds AP1 and AP3, the main adaptor proteins facilitating the
trafficking of membrane proteins from the trans Golgi network to
the lysosomes [93,94]. A second, unconventional lysosomal targeting
motif of CLN3, [MetX9Gly, where X can be any amino acid except Pro or
Asp] was found in the C-terminal cytoplasmic domain [85]. Additionally, C-terminal prenylation of CLN3 is involved in the endosomal
sorting of the protein [86].
The proposed functions of CLN3 include lysosomal acidification,
lysosomal arginine import, membrane fusion, vesicular transport,
cytoskeletal linked function, autophagy, apoptosis, and proteolipid
modification. Yeast models have been extensively utilized to study the
function of CLN3 and S. cerevisiae and S. pombe with a deletion in the
CLN3 homologue, (btn1-Δ), exhibit altered vacuolar pH [95–97].
Lysosomal pH has been shown to be affected also in human fibroblasts
of juvenile NCL patients (JNCL) and collectively these data implicate
that CLN3/Btn1p participates in the maintenance of lysosomal pH
[37]. Additional studies utilizing both S. pombe and S. cerevisiae
further propose a link between CLN3/Btn1p and vacuolar/lysosomal
ATPase functions [97,98]. Moreover, a deficiency of intracellular
arginine and lysine was observed in the btn1-Δ yeast, suggesting a
role of Btn1p in the inward transport of basic amino acids across the
vacuolar membrane [99]. These data were supported by experiments
with isolated lysosomes of JNCL cells showing that inward transport of
arginine was defective and decreased arginine levels were found in
the serum of Cln3−/− mice [100,101]. More recent studies in S. pombe
have exposed further functional roles for Btn1/CLN3, including
regulation of vacuolar fusion or size, cytokinesis, endocytosis,
polarized localization of sterol-rich membrane domains and polarized
growth [97,102]. Studies in mammalian cells have also indicated
involvement of CLN3 in cytoskeletal organization, endocytosis and
lysosomal size [103,104]. The S. cerevisiae Btn1-Δ strain showed gross
up-regulation of Btn2 encoding Btn2p [96] and CLN3 has been shown
to interact with its mammalian homolog, Hook1 [103]. The function of
Hook1/Btn2p has also been linked to membrane fusion events
because Hook1 has been shown to interact with several Rab GTPases
[103,105] and Btn2p binds to SNARE proteins in yeast [106]. Therefore,
CLN3 may also contribute to membrane fusion and this is supported
by the fact that both fluid-phase and receptor-mediated endocytosis
are impaired in CLN3/Cln3 deficient cells [103,107].
CLN3 may also be involved in the maturation of autophagic
vacuoles [108]. Mitochondria can be engulfed by autophagosomes
which fuse subsequently with lysosomes. Whereas mitochondrial
functions are not affected per se in Cln3−/− mice, it has been reported
that the size of mitochondria is enlarged [109]. CLN3 function has also
been linked to the cytoskeleton based on transcript profiling
experiments, due to the interaction with the microtubulus binding
Hook1 and the observed impaired axonal transport in the optic nerve
in Cln3-deficient mice [47,103,109–111]. Recent observations have
further connected CLN3 to fodrin-mediated endocytosis of Na+, K+
ATPase [112]. CLN3 has also been linked to apoptotic and autophagic
mechanisms of cell death [113–115]. Down-regulation of CLN3 has
been reported to be associated with an increased rate of apoptosis
[116,117]. Furthermore, the calcium-binding protein, calsenilin, was
reported to interact with the C-terminal domain of CLN3 and its
overexpression contributed to cell death in Cln3 knockdown cells
[118]. JNCL, like all the NCL disorders, show accumulation of
proteolipid compounds and palmitoyl-protein Δ-9 desaturase activity
has been reported for CLN3 [117]. Therefore, CLN3 may well be
involved in proteolipid modification. However, further investigations
are needed to accurately define the operation of CLN3 in the
endosomal/lysosomal pathway.
4.2. CLN3 disease
Mutations in the CLN3 gene result in juvenile neuronal ceroid
lipofuscinosis (JNCL, Batten disease, MIM#204200 [83]. JNCL represents the world-wide most common form of NCL. Currently, more
than 40 mutations have been characterized in the CLN3 gene (http://
www.ucl.ac.uk/ncl). The world-wide most common mutation causes a
1 kb deletion in CLN3, resulting in the deletion of two exons. Although
this mutation is predicted to produce a severely truncated polypeptide, recent analyses have proposed a residual function for this mutant
protein [104]. Disease-causing mutations usually cause ER retention of
the mutated protein [119], however, some disease mutations
correlating to milder phenotypes of JNCL, allow the mutated CLN3
to leave the ER [119,120]. JNCL usually begins with visual failure due to
retinal degeneration at 5–10 years of age. Mental retardation develops
slowly and is followed by epilepsy and deterioration of motor skills.
Juvenile NCL is also connected to different psychiatric symptoms like
aggressiveness, depression and sleep problems [9]. The clinical course
is largely variable and the death occurs in the second or third decade.
At autopsy, the cerebral cortex is narrowed and the weight of the brain
is decreased. Electron microscopy reveals fingerprint profiles (FPP)
[121] which can be detected already in chorion villus samples [223]
and the storage deposits contain mainly subunit c of the mitochondrial ATP synthase [224]. JNCL disease is the only NCL disorder typified
by vacuolated lymphocytes [11].
4.3. CLN3 animal models
Four mouse models exist for JNCL, one with deletion of the mouse
Cln3 exons 1–6 (Cln3−/− mice) [122, Table 2] and two with deletion of
exons 7–8 (Cln3Δex 7–8 mice) [123], and Cln3 knockout mice [124]. The
fourth model (Cln3 knock-in reporter) is characterized by deletion of
exons 1–8 and containing the β-galactosidase gene as a reporter [125].
These mice accurately replicate the cellular pathology of JNCL and it
A. Jalanko, T. Braulke / Biochimica et Biophysica Acta 1793 (2009) 697–709
appears that the models mimicking human mutations present with a
slightly more severe phenotype [17]. Cln3−/− mice display a selective
loss of inhibitory interneurons and early low level glial activation
which precedes neuron loss [122,129]. Consistent with other forms of
NCL these pathological changes are most pronounced in the
thalamocortical system [128,129]. Recent evidence suggests that
pathological changes within the optic nerve and thalamus are
responsible for visual failure in murine JNCL [110]. Characteristic for
human JNCL, the Cln3−− mice also display an autoimmune response
[130,131]. The autoantigens can gain access to the CNS via a sizeselective breach in the blood brain barrier [132], although their
pathological significance remains unclear. The most recent phenotypic
characterization of the Cln3 knockout mouse reported significantly
shortened life spans, with behavioural changes including reduced
spontaneous activity levels and impaired learning and memory [127].
The Cln3 knock-in reporter model was utilized to correlate gene
expression with pathology and behaviour and is expected to provide
valuable information related to CLN3 function [125]. Lowered binding
levels of N-methyl-D-aspartate- and M1-muscarinic acetylcholine
receptors were recently reported in select brain regions of Cln3Δex 7–
8
mice [126]. The Cln3 deficient mouse models will be a valuable
resource for characterizing therapeutic applications for JNCL. The
reported vulnerability of Cln3−/− neurons to AMPA-type glutamate
receptor overactivation was utilized in therapeutic approaches and
improvement in rotarod performance after injection of an AMPA
antagonist was reported recently [133,134].
CLN3 is a highly conserved protein and small invertebrate animal
models such as the Drosophila, may prove excellent models to track
the cellular defects mediated by CLN3 deficiency. To date, only worm
models have been utilized to analyze CLN3 deficiency. C. elegans
contains three CLN3 homologs, and these have been deleted
individually or all together. Similar to the ppt-1 mutant worms,
these mutants do not exhibit typical characteristics of NCL [135].
5. CLN5
5.1. CLN5 gene and protein
The CLN5 gene in chromosome 13q21–q32 encodes a 407 amino
acid CLN5 polypeptide with a predicted molecular mass of 46 kDa. CLN5
is not homologous to any known protein and its function is unclear
[136]. CLN5 contains four initiator methionines and in vitro translation
analysis of the CLN5 cDNA demonstrated the production of four
polypeptides with apparent molecular masses from 39 to 47 kDa
[63,137]. CLN5 contains eight potential N-glycosylation sites and the
glycosylated CLN5 protein shows an apparent molecular mass of 60–
75 kDa with both high-mannose-type as well as complex-type sugars
[63,137]. Controversial data has been reported about the solubility of
the CLN5 protein [13,138], but human CLN5 has been found to contain
mannose 6-phosphate residues on high-mannose type oligosaccharides linked to Asn320, Asn330, and Asn401 [139] supporting the
existence of soluble CLN5 variants. Additionally, the mouse Cln5 protein has been shown to be soluble [140]. The subcellular localization of
overexpressed CLN5 has been reported to be lysosomal [63,137, Fig. 1].
Similarly to PPT1 (CLN1) and CLN3, the localization of CLN5 was
reported to be different in neurons where the protein was observed in
axons in addition to lysosomes [140]. Overall, the CLN5 protein is not
well conserved, lacks protein homologues and is currently rather
poorly characterized. Co-immunoprecipitation and in vitro binding
assays have shown that CLN5 interacts with both CLN2 and CLN3, thus
providing the first molecular link between NCL proteins [63].
5.2. CLN5 disease
The Finnish variant form of late infantile neuronal ceroid
lipofuscinosis (vLINCLFin, CLN5, MIM#256731) is caused by mutations
701
in the CLN5 gene [136]. Thirteen different CLN5 mutations are so far
known in vLINCL patients [136,138,141–143] (http://www.ucl.ac.uk/
ncl). The major mutation (CLN5Fin major) was identified in 94% of
Finnish disease chromosomes. It is a 2 bp deletion in exon 4
(c.1175delAT) resulting in a stop codon at Tyr392 in the corresponding
polypeptide. Clinical phenotype of European patients with mutations
in CLN5 has been reported to be highly similar and currently it is not
known whether any residual CLN5 function would remain in any of
the cases. The spectrum of clinical development was broad even
between patients with identical mutations, but no distinct difference
was observed in the clinical spectrum [141]. Interestingly, the Arg112
has been reported to be mutated in two different cases (p.Arg112Pro;
p.Arg112His), possibly indicating a mutation hotspot region or an
important structural role for this residue. The first symptoms of the
disease, i.e. motor clumsiness followed by progressive visual failure
and blindness, have been observed between 4 and 7 years of life. Other
symptoms include motor and mental deterioration, myoclonia and
seizures. This disease results also in an early death, between the ages
of 14 and 36 years [144,145]. The major storage component in CLN5
patients is subunit c of the mitochondrial ATP synthase complex [146],
and the ultrastructure of the lysosomal storage material, consists of
CLP and FPP [2].
5.3. CLN5 animal models
The CLN5 gene is quite conserved among mammals and eukaryotes
but to date the only animal models are from mammalian origin,
namely the Cln5−/− knockout mice [147, Table 2] and the naturally
occurring canine, sheep and cattle models [148–150]. The Cln5−/−
mice exhibit rather mild clinical symptoms, in accordance with the
milder NCL-phenotype in human vLINCLFin patients. The mice show
accumulation of autofluorescent material in the CNS, with typical
ultrastructure of FPP and CLP. Gene expression profiling of adult Cln5
−/−
mouse brains revealed changes in the expression levels for genes
that where related to inflammation, myelin integrity and neuronal
degeneration [147]. Detailed information about the neuropathological
changes in the Cln5−/− mouse has, however, been missing until now.
Transcript profiling analyses suggested a close relationship between
Cln1 and Cln5 models, implicating a common affected pathway
mediated by phosphorylation and potentially affecting the maturation
of axons and neuronal growth cones [48]. The large animal models, i.e.
cattle, sheep and dogs, present with a disease course matching CLN5,
the fluorescent storage bodies show ultrastructure of CLP and FPP and
storage of subunit c [148–150]. A more profound characterization of
the neuropathology in the large CLN5 animals is yet to be
accomplished.
6. CLN6
6.1. CLN6 gene and protein
The CLN6 gene is located on chromosome 15q23, and spans
∼22.7 kb containing seven exons which produces a single 2.4 kb
mRNA [151,152]. This gene encodes a non-glycosylated 27 kDa
polytopic membrane protein, CLN6, of 311 amino acids which is
localized in the endoplasmic reticulum (ER) [153,154, Fig. 1]. In
neuronal cells, the protein is additionally found along neural
extensions in subdomains of a tubular ER network [155]. CLN6
contains an N-terminal cytoplasmic domain, seven putative transmembrane domains, and a luminal C-terminus. Mutational analysis
has shown that CLN6 contains two ER retention signals, one comprises
the N-terminal 49 amino acids and a second dominant motif consists
of a distal pair of transmembrane domains. Cross-linkage experiments
have shown that CLN6 forms homodimers [153]. The half-life of CLN6
has been determined to be about 34.5 h (A. Kurze et al., unpublished
results).
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6.3. CLN6 animal models
Fig. 1. Preferential subcellular localization of NCL proteins — CLN1, CLN2, CLN3, CLN5,
CLN7, CLN10 (cathepsin D, CtsD) and CLC7 are mainly localized in lysosomes (vacuoles
in yeast) whereas CLN6 and CLN8 are found in the endoplasmic reticulum (ER).
Depending on the expression level, the cell type investigated, and the transport kinetics,
small amounts of NCL proteins can be found at steady state also in other compartments
such as CLN8 in the ER–Golgi intermediate complex (ERGIC) [172] or CLN3 in
endosomes and at the plasma membrane [85,86]. e.E., early endosomes; l.E., late
endosomes; cGN, cis Golgi network; mg, mid Golgi; tGn, trans Golgi network.
CLN6 represents a conserved protein among vertebrates bearing
no functional or sequence homologies with other proteins. At present
it is unclear how mutant CLN6 leads to lysosomal dysfunction. Neither
trafficking nor processing of different newly synthesized lysosomal
hydrolases was affected in CLN6-defective fibroblasts [153]. In
contrast, the receptor-dependent uptake of the recombinant lysosomal enzyme arylsulfatase A was increased which might be due to
alterations in the intracellular distribution of M6P receptors, and in
the concentration and distribution of endocytic adaptor proteins or
membrane components involved in sorting and trafficking of cargo
receptors along specific routes. Furthermore, the intracellular degradation of endocytosed proteins appear to be reduced which might be
related to the finding on increased lysosomal pH in CLN6-defective
fibroblasts [37] and impairs both maturation and enzymatic activity of
lysosomal hydrolases.
There are natural animal models such as the nclf mouse, the New
Zealand South Hampshire sheep (OCLN6), and the Merino sheep
carrying defects in CLN6 orthologous genes. The course of their
neurodegenerative phenotype resembles the human CLN6 disease
[151,152,158–160, Table 2]. A frameshift mutation (c.307insC) in the
Cln6 gene underlies the NCL phenotype in nclf mice resulting in the
synthesis of a short-lived truncated Cln6 protein (A. Kurze et al.,
unpublished results). Progressive retinal atrophy with onset at
4 months, motor dysfunctions with spastic limb paresis at 8 months
and paralysis and death by 12 months are observed. Lipid analyses
have shown that the gangliosides GM2 and GM3 accumulate with age
[161]. Microarray studies of brain cortex from presymptomatic nclf
mice revealed reduced expression levels of GABAA2 receptor subunits
and components of the intracellular vesicular transport machinery (A.
Quitsch et al., manuscript in preparation). The gene defect in the New
Hampshire ovine model of CLN6 is localized on sheep chromosome
7q13–15 which is synthenic with the human CLN6 gene [162]. The
ovine CLN6 gene is 90% homologous to that in humans but the
disease-causing mutation has not been identified yet [160]. Specific
lysosomal storage of subunit c of mitochondrial ATP synthase was first
observed in these sheep [158]. The progressive and regionally defined
neurodegeneration in these sheep is marked by gross atrophy, cortical
thinning and neuronal loss from 2 months of age [163]. Early
prominent activation of astrocytes and microglial cells has been
observed, however, prenatally preceding neuronal loss and atrophy
[163,164]. Activated microglia serve as indicator of local neuronal
damage and might be linked to the up-regulated expression of the
radical scavenger manganese-dependent superoxide dismutase in
CLN6 defective cells and tissues [165]. Retinal degeneration and loss of
photoreceptor cells and the first clinical symptoms develop between
10 and 14 months of age [158]. Recent 1H NMR spectroscopy and GCMS based metabolomic investigation showed that glutamine and
succinate concentrations increased in all examined brain regions
during the postnatal life whereas aspartate, acetate, glutamate, Nacetyl aspartate and GABA decreased in affected sheep [166] similarly
to metabolite changes observed in Cln3−/− mice [167]. The reduction
in GABA concentration parallels the loss of specific GABAergic
interneurons in affected brains [168]. NCL was also diagnosed in
Australian Merino sheep with a similar aetiology to that in South
Hampshire sheep which is caused by a missense mutation (c.184C N T;
p.Arg62Cys) in the ovine CLN6 gene [160].
6.2. CLN6 disease
7. CLN7
Mutations in the CLN6 gene cause a variant late infantile
neuronal ceroid lipofuscinosis (vLINCL; MIM#601780). Twenty
seven disease-causing mutations have been described at present
(NCL Mutation Database www.ucl.ac.uk/ncl/mutation). The most
common mutation in CLN6 patients in Costa Rica represents a
nonsense mutation c.214G NT (p.Glu72X). Expression studies of
different missense mutations in CLN6 result in reduced stability and
degradation most likely by proteasomes (A. Kurze et al., unpublished results). CLN6 patients originate mostly from Eastern Europe
(Czech Republic), Pakistan, and Portugal [3]. Few cases has been
identified in France, Italy, Brazil and Turkey [156,157]. The age of
onset of CLN6 is between 18 months and 8 years and the leading
symptoms were motor delay, dysarthria, and ataxia. In approximately 65%, seizures started before the age of 5 years. Visual failure
occurred early in 50% of patients. Deterioration is rapid after
diagnosis and most children die between the ages of 5 and 12 years.
Examination of post mortem brain of CLN6 patients revealed
atrophy proportional to the length of the symptoms with a marked
neuronal loss in layer V of the cerebral cortex. The ultrastructure of
the cerebral neuronal storage material is a mixture of RLP and FPP
containing the subunit c of mitochondrial ATP synthase [15].
7.1. CLN7 gene and protein
The CLN7 gene has been identified recently by genome-wide scan
and homozygosity mapping and is located on chromosome 4q28.1–
q28.2 with a main transcript of ∼ 5 kb [5]. This gene encodes an
evolutionary conserved 58 kDa protein, CLN7, with 12 predicted
transmembrane domains. CLN7 contains 518 amino acids and belongs
to the large major facilitator superfamily (MFS) transporting specific
classes of substrates, including sugars, drugs, inorganic and organic
cations, and various metabolites [169]. The substrate specificity of
CLN7, however, remains to be elucidated. The overexpressed CLN7 is
localized in lysosomes [5, Fig. 1].
7.2. CLN7 disease
Mutations in the CLN7 gene cause the Turkish variant late
infantile neuronal ceroid lipofuscinosis (vLINCL; MIM#610951). Six
homozygous disease-causing mutations in five families have been
described at present (NCL Mutation Database www.ucl.ac.uk/ncl/
mutation). Similar to other forms of vLINCL, CLN5, CLN6 and CLN8,
A. Jalanko, T. Braulke / Biochimica et Biophysica Acta 1793 (2009) 697–709
the age of onset ranges from 2 to 7 years. The initial symptoms are
most commonly severe epileptic seizures. Progressive cognitive and
motor deterioration, myoclonus, personal changes and blindness
lead to premature death. On electron microscopic analysis, CLN7
patients have shown condensed FPP or RLP in storage material of
circulating lymphocytes [170].
8. CLN8
8.1. CLN8 gene and protein
The CLN8 gene is located on chromosome 8p23, and contains three
exons which produce three RNA transcripts by alternative splicing in
the 3′UTR [171]. This gene encodes a non-glycosylated 33 kDa
polytopic membrane protein, CLN8, of 286 amino acids and the
overexpressed protein is localized primarily in the ER but has been
suggested to shuttle between the ER and ER–Golgi intermediate
complex (ERGIC) [172, Fig. 1]. The retrieval of CLN8 from ERGIC to
the ER is mediated by a di-lysine motif, KKRP, that is localized in the
cytoplasmic C-terminal domain. In mouse hippocampal neurons,
the protein is localized mainly in the ER [173]. When overexpressed in
the polarized epithelial CaCo-2 cell line CLN8 appeared to be localized
in a subcompartment of the ER close to the plasma membrane [173].
The exact function of CLN8 is unknown, but it belongs to the TRAMLag1p-CLN8 (TLC) family of proteins, members of which are suggested
to have roles in biosynthesis, metabolism, transport, and sensing of
lipids [174,175]. Proteins within this family have a conserved domain
structure with at least five transmembrane domains. Cross-linkage
experiments have shown that CLN8 forms homodimers [155].
epileptic seizures were not observed. The age of onset, the progression
rate, neurological symptoms, and the affected cell types appear to
depend on the genetic background of mnd mice [182,183]. Changes in
lipid metabolism observed in EPMR patients also appear to be present
in the mnd mouse as well as increased concentrations of oxyradicals
and lipid peroxides [184–186]. Furthermore, several observations in
presymptomatic mnd mice suggest that alterations in the glutamatergic neurotransmission may contribute at an early stage to motor
neuron degeneration [187–189]. In addition to mnd mice, in English
Setter dogs a missense mutation (c.491T N C) in the Cln8 gene has been
reported that causes an NCL phenotype [190].
9. CLN9
9.1. CLN9 disease (MIM #609055)
Four patients have been described presenting clinical features
identical to those seen in juvenile or CLN3-deficient patients. The
CLN9 gene, however, is still unknown. Fibroblasts of these patients
have a distinctive phenotype and grow rapidly, are sensitive to
apoptosis, manifest a cell adhesion defect, and exhibit reduced levels
of ceramide, dihydroceramide, and sphingomyelin [191]. DNA array
analysis revealed dysregulated genes involved in cell cycle control, cell
adhesion and apoptosis. Partial correction of growth and apoptosis
sensitivity was achieved by transfection with CLN8 cDNA containing
Lag1 sequence homologies necessary for ceramide synthesis in yeast
[192]. These data combined with sphingolipid activator studies
suggest that the CLN9 protein may be a regulator of dihydroceramide
synthase [193] and might be functionally related to CLN8.
8.2. CLN8 disease (MIM#600143)
10. CLN10
CLN8 is mutated in Finnish families with Northern epilepsy
(progressive epilepsy with mental retardation, EPMR) and in Turkish,
Italian and Israelian patients with more severe variant late infantile
NCL [171,176–178]. Eleven mutations have been identified in CLN8
(NCL Mutation Database www.ucl.ac.uk/ncl/mutation). All but one
Finish EPMR patients are homozygous for a missense mutation
(c.70C N G) in the CLN8 gene resulting in arginine to glycine
substitution at codon 24 (p.Arg24Gly) [171]. It appears that this
mutation causes a protected and atypical NCL [11]. The first symptoms
in Finish CLN8 patients, epileptic seizures, are observed at the age of 5
to 10 years. All patients have generalized tonic–clonic seizures that
may last up to 15 min. The frequency of the epileptic seizures increases
to 1–2 seizures per week in puberty [179] accompanied with
progressive mental deterioration and motor problems. Progressive
cerebellar and brain stem atrophy is manifest already in young adults
[180]. The patients may survive until 50–60 years of age. Retinal
degeneration, a characteristic finding in NCL, has not been reported in
EPMR patients. In contrast, the Turkish patients with CLN8 mutations
show a more typical NCL phenotype including loss of vision [170]. The
storage material in CLN8 patients consists mostly of subunit c of
mitochondrial ATP synthase and shows CLP. Mass spectrometric
analysis of brain samples of EPMR patients revealed changes in the
molecular composition of several phospho- and sphingolipid classes
[181] which might lead to altered membrane properties and affect
functions of membrane proteins such as release and uptake of
neurotransmitters.
10.1. CLN10 gene and protein
8.3. CLN8 animal models
There exists a natural mouse model, the motor neuron degeneration (mnd) mouse, that has a one base pair insertion, c.267–268insC,
in the orthologous mouse Cln8 gene resulting in a frameshift and
predicts a stop codon after 27 amino acids [171, Table 2]. Mnd mice are
characterized by retinal degeneration and severe paralysis whereas
703
The CLN10 gene is located on chromosome 11p15.5 and encodes
the major lysosomal aspartic protease cathepsin D (CTSD). Human
CTSD contains 412 amino acid residues and is synthesized as a 53 kDa
inactive preproenzyme which becomes posttranslationally modified
by glycosylation, mannose 6-phosphate (M6P) residues, and limited
proteolysis leading to 47, 31 and 14 kDa intermediate and mature
enzyme forms, respectively [194]. Rat and mouse Ctsd exist
predominantly as a single chain 47 kDa polypeptide. Dependent on
the cell type CTSD is transported to lysosomes in an M6PR-dependent
and -independent manner [195,196, Fig. 1]. CTSD is involved in limited
proteolysis rather than in bulk lysosomal proteolysis [197] and its
enzymatic activity can be specifically inhibited by pepstatin A. Several
proteins are described to function as substrates of CTSD in vitro,
including prosaposin (proSAP) which can be cleaved into saposins A,
B, C, and D [198]. Saposins A to D are essential cofactors for the
hydrolysis of certain sphingolipids [199]. In vivo substrates of CTSD,
however, are still unknown. In addition to its proteolytic activity, CTSD
has been implicated in many biologically important processes related
to cell proliferation, antigen processing, apoptosis, and the regulation
of plasma HDL-cholesterol level [200–203].
10.2. CLN10 disease (MIM #610127)
Mutations in the CLN10 gene have been described recently in three
patients with both congenital NCL and with a severe course of
neurodegeneration beginning at early school age [4,6]. Four diseasecausing mutations have been described at present (NCL Mutation
Database www.ucl.ac.uk/ncl/mutation). Ten patients with congenital
NCL inherited in an autosomal recessive manner have been reported
so far although they have not been genetically defined [3]. Clinically
these patients present at birth respiratory insufficiency, rigidity, status
epilepticus, and death occurs within hours to weeks after birth. Upon
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autopsies, microcephaly accompanied by massive loss of neurons in
the cerebral cortex, extensive gliosis, absence of myelin and
autofluorescent storage bodies with a GROD ultrastructure have
been observed. Additionally, CTSD deficiency in one German patient
has been described presented with visual disturbances and ataxia at
early school age followed by a progressive psychomotor decline.
Compound heterozygosity of two missense mutations in the CLN10
gene leads to residual CTSD activity [6] which may be responsible for
the retarded course of the disease in this patient.
thought that the highly glycosylated Ostm1 β-subunit protects the
non-glycosylated ClC-7 from lysosomal degradation [219]. Recently
it has been demonstrated that native lysosomal membranes display
Cl−/H+-exchange activity that most likely represents ClC-7 [220].
Although ClC-7 has been hypothesized to be important for
lysosomal acidification, steady state lysosomal pH was not changed
in the absence of ClC-7 or its β-subunit Ostm1 [216,219]. ClC-7 is
ubiquitously expressed with high expression levels in the pyramidal
cell layer in the hippocampus and in Purkinje and granule cells in
the cerebellum [215,216].
10.3. CLN10 animal models
11.2. CLCN7 disease
Several animal models exist with mutations in the Cln10 gene
exhibiting symptoms of severe congenital NCL, such in White Swedish
Landrace sheep [204], or with less severe late onset NCL in American
Bulldogs [205]. The best studied animal model, however, is the cathepsin D knockout (ctsd−/−) mouse presenting a very aggressive NCL
phenotype in which also visceral organs are affected [197, Table 2].
The ctsd−/− mice develop normally until the age of 2 weeks followed
by rapid onset of severe seizures and blindness. The induction of
seizures has been linked to impaired GABAergic neurotransmission
and reduced concentration of GABA in the hippocampus of ctsd−/−
mice [206]. Finally the mice die in a state of anorexia at an age of 26
± 1 days. In ctsd-deficient CNS, neurons and glial cells contain large
autofluorescent bodies and accumulate ceroid/lipofuscein, the subunit c of mitochondrial ATP synthase, GM2 and GM3 gangliosides, and
highly elevated level of the unusual lysophospholipid bis(monoacylglycero)phosphate [161,207]. Pathologic changes are particularly
pronounced within the thalamocortical pathways between ventral
posterior nucleus of thalamus and in neuronal laminae IV and VI of the
somatosensory cortex of ctsd−/− mice. These changes include
astrocytosis, microglial activation, loss of neurons and synapses, and
axonal degeneration [208]. Although the exact mechanism of
neuronal and photoreceptor cell death is not clear a profound increase
in the number of autophagosomes/autolysosome-like bodies has been
reported [207,209]. The intrinsic as well as Bax-dependent death
receptor-activated apoptotic pathway, however, appears to be not
critical for the neuron loss induced by ctsd-deficiency [210].
Compensatory increases in the levels and activity of cathepsin B and
tripeptidyl peptidase-I, lysosomal membrane permeabilization, and
the promotion of an inflammatory response mediated by glial cell
activation and oxidative stress are likely candidates for non-apoptotic
death mechanisms in ctsd−/− mice [207,211].
Cathepsin D-deficient sheep are severely affected at birth and die
within a few days [204]. A homozygous missense mutation in the ctsd
gene changes in the encoded protein an active site aspartic acid to
asparagines (p.Asp293Asn) resulting in an enzymatically inactive but
stable protease [212]. The targeting of the Cln10 gene in D.
melanogaster did not affect the development, viability, fertility or
lifespan of the fly but led to a progressive accumulation of
autofluorescent storage material in the brain with modest age-related
neurodegeneration [213].
Mutations in the CLCN7 gene were found in a subpopulation of
children with a severe autosomal recessive infantile malignant
osteopetrosis (ARO, MIM#259700) and fatal outcome within the first
decade of life. More than 30 disease-causing mutations have been
reported in the CLCN7 gene [221,222]. The osteopetrosis results from
deficits in bone resorption due to osteoclast malfunction. Other clinical
manifestations are cerebral atrophy, macroencephaly, autism, deafness
and blindness [221]. The development of blindness and severe CNS
degeneration even if the osteopetrosis in a small number of patients is
successfully treated by bone marrow transplantation suggest that the
CNS abnormalities are directly related to CLCN7 mutations.
11.3. CLCN7-defective animal model
Mice with a disruption of the Clcn7 gene showed severe
osteopetrosis, retinal and neuronal degeneration, and lysosomal
accumulation of storage material, and die within 7 weeks of life
[215,216]. Their osteopetrosis is caused by dysfunctional osteoclasts
that fail to acidify the resorption lacuna leading subsequently to
deficits in the degradation of bones. The retina of Clcn7−/− mice
degenerates within the first 2–4 weeks after birth resulting in an
almost complete loss of photoreceptors at an age of 28 days [215]. The
retinal degeneration was independent of the osteopetrosis because
the transgenic rescue of the osteopetrosis failed to prevent the loss of
photoreceptors [216]. ClC-7 is localized in cortical and cultured
hippocampal neurons in lysosomes colocalizing with Lamp-1 [216].
The degeneration of CA3 pyramidal cells by postnatal day 40 close to
the death of the Clcn7−/− mice is paralleled by an activation of
microglia. Autofluorescent material was found predominantly in CA3
region of the hippocampus, underneath the corpus callosum, in the
cerebral cortex and the thalamus. GRODs and FPPs were already
observed at postnatal day 11. In addition, there was a strong
accumulation of subunit c of ATP synthase. The intralysosomal pH in
cultured neurons of Clcn7−/− mice was unchanged. Genome-wide
expression profiling in the hippocampus of 14 day old Clcn7−/− mice
revealed 52 dysregulated genes involved in antigen presentation,
complement components, and microglia/macrophage activation
[215].
12. CLCN3 and CLCN6
11. CLCN7
11.1. CLCN7 gene and protein
The CLCN7 gene is located on chromosome 16p3, and encodes a
non-glycosylated 89 kDa polytopic membrane protein, ClC-7, of 805
amino acids [214]. ClC-7 is a member of a highly conserved gene family
of chloride channels and transporters with orthologs from bacteria to
man (for review see [7]). ClC-7 is localized in late endosomes/
lysosomes [215,216]. ClC-7 contains two potential overlapping sorting
motifs promoting both the antero- and retrograde transport between
TGN and endosomes. ClC-7 binds to a small type I membrane protein,
Ostm1. In the absence of Ostm1 ClC-7 becomes unstable and it is
Defects in two other members of the CLC family, ClC3 and ClC6,
have been discussed to play a causative role in NCL (for review see
[217]). ClC3 is localized in endosomal membranes and synaptic
vesicles and functions as vesicular Cl−/H+-exchanger [218,225]. The
data on the disruption of the Clcn3 gene by three different groups
were controversial differing in the accumulation of subunit c of
mitochondrial ATP synthase, the spatial–temporal sequence of
hippocampal neurodegeneration, skeletal and metabolic abnormalities [218,226,227]. No patients have been identified yet with
mutations in the CLCN3 gene.
ClC6 is predominantly expressed in neurons of the central and
peripheral nervous system and is localized in late endosomes.
A. Jalanko, T. Braulke / Biochimica et Biophysica Acta 1793 (2009) 697–709
Targeting of the Clcn6 gene in mice revealed a progressive lysosomal
storage at 4 weeks of age associated with accumulation of lipofuscein
and subunit c of mitochondrial ATP synthase. The lysosomal pH was
normal and no loss of neurons has been observed. The mice are fertile,
visually not impaired, and had a normal life span resembling clinically
mild forms of NCL [228]. By sequencing of 75 patients, with late onset
NCL, however, only two heterozygous missense mutations have been
identified failing to prove a causative role of ClC6 in NCL.
13. Conclusions
The genome era has introduced a wide variety of technologies for
the search of protein function and disease mechanisms. Cell, yeast and
animal models have been widely utilized in NCL biology but the
functions of individual NCL proteins as well as the disease mechanisms underlying NCL are still largely unknown. Although the soluble
CLN1/PPT1 and CLN2/TPP2 and CLN10/cathepsin D have been
extensively characterized, their in vivo substrates still remain elusive.
The CLN5 protein is most likely a lysosomal enzyme with totally
unknown function. The transmembrane proteins CLN3, CLN6, CLN7
and CLN8 have been difficult to characterize, although CLN7 and CLN8
contain domains suggestive for transporter and lipid sensing functions, respectively. The CLN3 protein is highly conserved and yeast,
mammalian cells and mouse models have been extensively utilized to
demonstrate that this protein is involved in a variety of cellular
processes. The research of the chloride channel proteins ClC3, ClC6
and ClC7 has provided novel information about endosomal/lysosomal
acidification. Extended expression analyses of mutations identified in
patients with various NCL diseases combined with detailed description of the clinical phenotypes are required to define the association of
distinct mutations with the onset or the progression rates of the
diseases [11]. Animal models have provided valuable data about the
pathological characteristics and the most recent data of transcript,
lipidomic and metabolomic profiling suggest that disturbances in lipid
metabolism and GABA neurotransmission are common in several NCL
subtypes. New possibilities for genome-wide analyses and utilization
of public database resources should provide clues to perform deeper
characterization of the disease mechanisms in NCL and evidently will
also provide information on important pathways for neuronal
development and survival. The NCL mouse models are especially
useful for testing of different treatments and gene, enzyme and small
molecule-mediated treatment strategies and already have been
performed in Cln2-deficient mice and in CLN2 patients with some
initial good success.
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Further reading
[1] S.J. Kim, Z. Zhang, C. Sarkar, P.C. Tsai, Y.C. Lee, L. Dye, A.B. Mukherjee, Palmitoyl
protein thioesterase-1 deficiency impairs synaptic vesicle recycling at nerve
terminals, contributing to neuropathology in humans and mice, J Clin Invest. 118
(2008) 3075–3086.
[2] M.J. Oswald, D.N. Palmer, G.W. Kay, K.J. Barwell, J.D. Cooper, Location and
connectivity determine GABAergic interneuron survival in the brains of South
Hampshire sheep with CLN6 neuronal ceroid lipofuscinosis, Neurobiol. Dis. 32
(2008) 50–65.
[3] K. Oresic, B. Mueller, D. Tortorella, Cln6 mutants associated with neuronal ceroid
lipofuscinosis are degraded in a proteasome dependent manner, Biosci Rep. (2008),
doi:10.1042/BSR20080143.
[4] K. Fritchie, E. Siintola, D. Armao, A.E. Lehesjoki, T. Marino, C. Powell, M. Tennison, J.M.
Booker, S. Koch, S. Partanen, K. Suzuki, J. Tyynelä, L.B. Thorne, Novel mutation and
the first prenatal screening of cathepsin D deficiency (CLN10), Acta Neuropathol
(2008), doi:10.1007/s00401-008-0426-7.
[5] Pal, R. Kraetzner, T. Gruene, M. Grapp, K. Schreiber, M. Grønborg, H. Urlaub, S.
Becker, A. Asif, J. Gärtner, G. Sheldrick, R. Steinfeld, The structure of tripeptidyl
peptidase I provides insight into the molecular basis of late infantile neuronal
ceroid lipofuscinosis, J. Biol. Chem. (2008) in press.
[6] J. Guhaniyogi, I. Sohar, K. Das, A.M. Stock, P. Lobel, Crystal structure and
autoactivation pathway of the precursor form of human tripeptidyl-peptidase 1,
the enzyme deficient in late infantile ceroid lipofuscinosis, J. Biol. Chem. (2008) in
press.
[7] R.I. Tuxworth, V. Vivancos, M.B. O'Hare, G. Tear, Interactions between the juvenile
Batten disease gene, CLN3, and the Notch and JNK signalling pathways, Hum Mol
Genet. (2008) in press.