Amin et al., Brain Disorders Ther 2012, S:1
http://dx.doi.org/10.4172/2168-975X.S1-002
Brain Disorders & Therapy
Review Article
Open Access
Septin Phosphorylation and Neuronal Degeneration; Role of Cyclin Dependent
Kinase 5 (Cdk5)
Niranjana D Amin1, Philip Grant1, Yali Zheng2, Sashi Kesavapany3 and Harish C Pant1*
1
Laboratory of Neuronal Cytoskeleton Protein Regulatory Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
20892, USA
2
Departments of Nephrology, Ningxia People’s Hospital, Yinchuan, Ningxia 750021, China
3
Neurobiology Program, Department of Biochemistry, Yong Loo Lin School of Medicine, 11 Medical Drive, Singapore 117597, Singapore
Abstract
It is evident from the literature that most cellular functions are mediated by protein phosphorylation. It has also
been demonstrated that abnormal phosphorylation of neuronal cytoskeletal proteins often leads to the pathology of
several neurodegenerative diseases. For example, hyperphosphorylation of microtubule associated tau protein by
Cdk5 and other kinases such as GSK3 has been linked to the formation of neurofibrillary tangles (NFTs) associated with
Alzheimer’s disease (AD). Septins, a family of cytoskeletal proteins, also expressed in mammalian neurons, are involved
in synaptic function and have also been linked to various neurological disorders. Although Sept5 phosphorylation by
Cdk5 at the synapse has been reported to modulate exocytotic function, as yet, its phosphorylation has not been linked
to hyperactivated Cdk5 as seen in AD. The present review begins with an overview of Cdk5 function in the nervous
system, its role in neurodegeneration and its relationship to neuronal septins, their function and role in neurological
disorders. In a summary speculation, we attempt to correlate synaptic function of Cdk5 phosphorylation of septins that
may play a role in the etiology of neuronal disorders.
Keywords: Cdk5; Alzheimer’s disease; Parkinsons disease;
Amyotrophic Lateral Sclerosis (ALS); Septin; Phosphorylation;
Neurodegeneration; Synapse
Introduction
Cellular function is tightly regulated by protein kinases that
orchestrate cell signaling events [1]. During cell replication, kinases
activated by cyclin family members (Cdks) play an important role in
regulating transitions through the cell cycle in most organisms. Cdks
are activated upon association with cyclin regulatory subunits coupled
to a phosphorylation event at specific activation sites [2,3]. Cdk5,
though a member of the Cdk family, plays an important role outside
the cell cycle. It is activated by non cyclin proteins, p35 and p39,
which are predominantly expressed in the brain [4-8]. Though there
are few sequence similarities between p35/p39 and regulatory cyclins,
structural studies have shown that p35 assumes a cyclin like fold [9-11].
Cdk5 plays a key role in neuronal development and function including
neuronal migration, neurite extension, and synapse formation, as well
as synaptic activities in mature neurons [12-15]. Cdk5 phosphorylates
neuronal cytoskeletal proteins tau and neurofilaments [16,17]. In
neuronal migration, Cdk5 modulates actin dynamics, microtubule
and transport phenomena via phosphorylation of multiple substrates.
For example, phosphorylation of FAK at S732 (serine 732) is
necessary for microtubule organization, nuclear translocation, and
neuronal migration [18]. Phosphorylation of double cortin (Dcx)
at S297 modulates its association with microtubules and regulates
their polymerization [19]. A most prominent target of Cdk5 is tau, a
microtubule associated protein [20]. Excessive phosphorylation of tau
by deregulated Cdk5/p25 is crucially implicated in pathogenesis of AD
[21,22].
Synaptic functions of Cdk5 in mature neurons have been shown
with p35 knockout mice, a conditional knockout of Cdk5, and
conditional expression of p25, a C-terminal fragment of p35 [13,2325]. Cdk5 phosphorylation modulates synaptic transmission, neuronal
excitability, dendritic spine morphogenesis, and has been linked to
learning and memory [13]. It is clear from its extensive repertoire
of target substrates that Cdk5 activity is a key player in the nervous
Brain Disorders Ther
system; hence, its activity must be tightly regulated. Moreover, it has
become increasingly clear that deregulation of Cdk5 activity promotes
the pathological hallmarks of neurodegenerative diseases such as AD
[22], Parkinson’s disease (PD) [26] and Amyotrophic Lateral Sclerosis
(ALS) [27,28].
Cdk5 involvement in synaptic function and plasticity depends
upon its regulation of intracellular transport processes such as
endocytosis and exocytosis. Its role at the pre-synaptic compartment
is complex; it is involved in endocytic recycling of synaptic vesicles
by rephosphorylating dephosphins like the GTPase dynamin C [2931]. During exocytosis, several target proteins are phosphorylated by
Cdk5 [32-35] among which is Sept5; its phosphorylation by Cdk5 has
a profound effect on exocytosis. It is also evident that phosphorylation
of other neuronal septins may contribute to some of the pathogenesis
of neurodegeneration.
Septins
Septins are a conserved family of GTPases that were first found in
yeast as being essential for the completion of cell division [36-38]. The
name ‘Septins’ alludes to the widespread involvement of this family
of proteins in cytokinesis and septum formation. The discovery of a
complex world of cytoskeletal GTPases that play important roles in
human diseases emerged from the original discovery of four septin
proteins in the budding yeast Saccaromyces cerevisiae. Septins have been
*Corresponding author: Harish C Pant, Laboratory of Neuronal Cytoskeleton
Protein Regulatory Section, National Institute of Neurological Disorders and Stroke,
National Institutes of Health, Bethesda, MD 20892, USA; E-mail: [email protected]
Received July 12, 2012; Accepted August 25, 2012; Published August 27, 2012
Citation: Amin ND, Grant P, Zheng Y, Kesavapany S, Pant HC (2012) Septin
Phosphorylation and Neuronal Degeneration; Role of Cyclin Dependent Kinase 5
(Cdk5). Brain Disorders Ther S1:002. doi:10.4172/2168-975X.S1-002
Copyright: © 2012 Amin ND, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
Cdk5 and Brain Disorders
ISSN: BDT, an open access journal
Citation: Amin ND, Grant P, Zheng Y, Kesavapany S, Pant HC (2012) Septin Phosphorylation and Neuronal Degeneration; Role of Cyclin Dependent
Kinase 5 (Cdk5). Brain Disorders Ther S1:002. doi:10.4172/2168-975X.S1-002
Page 2 of 5
found in all eukaryotic organisms, with the exception of plants [39-41].
The most recent review describes septins as the fourth component of
the cytoskeleton [42] because of their filamentous appearance and their
association with cellular membranes, actin filaments and microtubules.
Thirteen septin genes have been identified in humans (Sept1Sept12 and Sept14, as Sept13 is now defined as a pseudo gene of
septin 7 (Sept7p2)) [43]. Many of these septin genes have alternative
splice variants [44] and have been subdivided into four groups based
on phylogeny. The septin 2 group (septins 1, 2, 4, and 5): the septin 3
group (septins 3, 9, and 12): the septin 6 group (septins 6, 8, 10, and 14)
and the septin 7 group consist only of septin 7. Figure 1 shows the basic
architecture of the longest known form of each of the 13 known human
septins and their structural diversity.
Directly adjacent to the variable N-terminal tail is a short polybasic
sequence followed by the highly conserved central GTPase domain that
spans most of the septin sequence; then a series of highly conserved
amino acids termed the septin unique element. In most septins, the
septin unique element is followed by a coiled-coil domain of variable
length [45]. The polybasic sequence is responsible for binding of
septins to membrane phospholipids [46]. Since all septins possess
a conserved GTP-binding domain, septins function as GTPasesignaling proteins related to their ability to bind and hydrolyze GTP.
In vitro studies showed that purified Drosophilla melanogaster septin
complexes strongly bound to GTP/GDP and had GTPase-activity, but
this GTP binding/exchange of D. melanogaster septin was found to be
very slow [47]. Individual recombinant septins and mammalian septins
showed faster GTP binding/exchange kinetics in vitro. All septins with
the exception of the septin 3 groups also contain a coiled-coil region
preceding the variable C-terminal tail [48]. The coiled-coil region of
yeast septins has been implicated in mediating interactions between
septins and other proteins [49]. In mammals, septins are expressed in
many tissues such as lung, spleen, testis, pancreas, liver, kidney and
brain.
Neuronal Expression and Functions of Septin
Based on the original yeast studies, septins play an important role
Septin 2 [361 aa]
Septin 3 [345 aa]
Septin 4 [478 aa]
PRD
Septin 6 [427 aa]
PB
Septin 7 [418 aa]
GBD
Septin 8 [752 aa]
SUD
CC
Septin 9 [586 aa]
Septin 10 [517 aa]
Septin 11 [429 aa]
Septin 12 [358 aa]
Septin 14 [432 aa]
Figure 1: The human septins. The longest known versions of the 14 human
septins described to date. All have a polybasic domain (PB), a GTP-binding
domain (GBD) and a septin unique domain (SUD). Some have a coiled-coil
domain at the C terminus (CC) and some have long N-terminal extensions with
regions rich in prolines (PRD).
Brain Disorders Ther
Phosphorylation of Septins
Protein phosphorylation, one of the fundamental mechanisms
governing diverse cellular function has a profound effect on septin
function. In the published reports several septins have shown to be
phosphorylated in vitro and/or in vivo [76-78,72]. For instance Sept1
is phosphorylated in vitro by aurora-B kinase [77]. Sept2 is a substrate
of casein kinase 2, and its phosphorylation on S218 is crucial for the
proliferation of hepatoma carcinoma cells [78]. Moreover, Sept2 is also
an in vitro substrate for protein kinase C and cAMP dependent protein
kinase A [59]. Sept3 phosphorylation on S91 by cGMP dependent
protein kinase G may contribute to the regulation of its subcellular
localization in neurons [72]. The in-depth research into Sept5 function
revealed that over expression of wild-type Sept5 in HIT-T15 cells
resulted in inhibition of regulated secretion, whereas over expression
of a dominant negative GTPase mutant S58A of Sept5, which cannot
bind to GTP, resulted in potentiation of exocytosis [58]. The dominant
negative phenotype of S58A Sept5 binds syntaxin more efficiently
compared to wild-type Sept5.
Septin 1 [367 aa]
Septin 5 [369 aa]
in cytokinesis [39,50-52]. Mammalian septins have been associated
with other cellular functions including apoptosis, vesicle trafficking,
cytoskeletal dynamics, cell polarity, and sperm motility [53-56].
Multiple septins discovery in adult brain and post-mitotic neurons
suggests that septins may have critical cellular functions in neurons.
Among all the septins, Sept2, Sept3, Sept4 Sept5, Sept6, Sept7, Sept8
and Sept11 are highly expressed in central nervous system [57].
Two septins, Sept3 and Sept5 express primarily in the brain [58-60].
However Sept5 is also present in platelets that suggest that Sept3 is the
only septin to date that is specific to the brain, as it is not found in
platelets or any other non neuronal cell lines [60,61]. Nine of the 13
septins in mammals (Sept2 to Sept9 and Sept11) have been found in
rat brain PSD fractions by mass spectrometry [57,62,63]. It has been
suggested that these septins are involved in dendritic maturation,
including spine morphogenesis and synaptic connectivity in cultured
hippocampal neurons [64-66]. A number of septins that are found
in post mitotic neurons have potential roles associated with synaptic
transmission. Sept7 is present in postsynaptic density fractions [67]
suggesting a role in cell architecture. One group, Sept6, Sept7, Sept2,
and Sept4, associates with the exocyst complex, which is involved in
polarized vesicle secretion function [50]. Sept5 and Sept2, have a role in
exocytosis and synaptic vesicle dynamics as both co-immunoprecipitate
with the snare protein syntaxin and synaptic vesicles [58,68,69]. Sept2
is a component of the exocyst complex [50] and ablation of its GTP
binding activity leads to altered neurite sprouting [70]. The Sept3/5/7
complex was identified in the mammalian brain and Sept3 specifically
is developmentally regulated and enriched in pre-synaptic nerve
terminals, suggesting a role for these septins in neuronal biology
[71,72]. Sept2 and Sept8 are associated with neurotransmitter release
due to their interaction with glutamate transporter (Glast) and the
synaptic vesicle protein synaptobravin 2(Vamp2) [73,74]. Expression
of several septins is developmentally regulated in cerebral cortex;
protein levels of Sept2, Sept5, Sept6, Sept7 and Sept8 gradually increase
at late embryonic stages through early postnatal days [73,65]. Recently,
Sept14 expression has been reported in the developing mouse brain
[75].
So far the phosphorylation of septins by Cdk5 has only been
reported for two isoforms of Sept5. In mice, Cdk5 phosphorylates S17
residue of adult type Sept5 [78]. However, that residue is not present
in the human fetal type Sept5. Human Sept5 has been phosphorylated
at the S327 residue instead [76]. Differences in secondary structure
Cdk5 and Brain Disorders
ISSN: BDT, an open access journal
Citation: Amin ND, Grant P, Zheng Y, Kesavapany S, Pant HC (2012) Septin Phosphorylation and Neuronal Degeneration; Role of Cyclin Dependent
Kinase 5 (Cdk5). Brain Disorders Ther S1:002. doi:10.4172/2168-975X.S1-002
Page 3 of 5
Septins
SP site
Position Sequence TP site
Position
Sequence
Septin 1
1
147
iSPfg
1
95
dTPgf
Septin 2
1
1654
iSPfg
1
14
eTPgy
Septin 3
1
179
iSPtg
1
126
dTPgf
Septin 4
1
100
iSPsa
1
209
dTPgf
Septin 5
1
161
iSPfg
1
12
aTPed
Septin 7
1
77
ySPey
1
114
dTPgf
Septin 8
0
1
156
iTPtg
Septin 9
1
39
pSPaq
1
1
1
71
91
199
aTPrs
dTPrd
dTPgf
Septin 10
1
180
iSPtg
0
Septin 12
1
28
30
39
rSPSP
pSPcl
sSPst
1
1
1
43
107
134
tTPce
pTPqt
dTPgf
Septin 14
1
166
iSPtg
0
Table 1: Human septins having proline directed kinase consensus Sequence: (ST)
PX(K/H/R).
may account for a different phosphorylation site in the two isoforms.
Nonetheless, phosphorylation of either site was reported to result
in decreased interaction of Sept5 with syntaxin 1 [78,76]. A S327A
mutation at the Cdk5/p35 phosphorylation site of human Sept5 results
in a more efficient binding to syntaxin 1 [76]. Furthermore, when
this non-phosphorylatable S327A mutant of Sept5 is over expressed
in PC12 cells, it yields an increased S327A mutation at the Cdk5/
p35 phosphorylation site of human Sept5 resulting in a more efficient
binding to syntaxin 1 [76]. Therefore, it appears that more efficient
interaction of Sept5 with syntaxin 1 results in potentiation of exocytosis,
whereas over expression of the wild type Sept5 inhibits secretion, and
this interaction is likely to be controlled by the phosphorylation state
of Sept5 [79]. These studies of Sept5 and its phosphorylation suggest
a strong link between Sept5 and the regulation of exocytosis. Though
Cdk5 phosphorylation of other septins awaits future experiments it
is appropriate to speculate that it may phosphorylate other septins
possessing a proline-directed consensus sequence as evident from table
1. The phosphorylation of Cdk5 may show its role in synaptic function
and disruption in synaptic function may lead to neurodegeneration.
Septins in Neurodegeneration
Septins are abundant in the central nervous system and are associated
with many neurological diseases such as Parkinson’s, Alzheimer’s,
Schizophrenia, and hereditary neuralgic amyotrophy (HNA) [80-84].
The brain specific expression of septins, their differential regulation
in neural development, their role in exocytosis and their association
with some disease states [85-88] suggest that abnormal septin function
may contribute to neurological disorders. Possible roles for septins in
neurological disorders have emerged based on the observation that
Sept2, Sept1 and Sept4 have been found in Alzheimer specific NFTs
[89]. Using proteomics, abnormalities of septin expression have also
been reported in Down’s syndrome [85]. The Sept5 interaction with
Parkin, a pathogenic protein in Parkinson’s disease [90,91], provides
evidence for the involvement of another subset of septins in neuronal
disease. Sept5_v2 has been reported to be a Parkin binding protein,
which may function as an E2-dependent ubiquitin ligase capable of
degrading Sept5. Sept5 accumulates in the brains of individuals with
autosomal recessive juvenile Parkinsonism [92]. Sept4 has also been
implicated in brain pathogenesis by its association with cytoplasmic
inclusions found in Parkinson’s disease and other synucleinopathies.
Sept2 and Sept8 are associated with neurotransmitter release due to their
interaction with glutamate transporter (Glast) and the synaptic vesicle
Brain Disorders Ther
protein synaptobravin 2(Vamp2) [73,74]. Other septin complexes
have been associated with myelin formation in the peripheral nervous
system. Recently a Sept9 point mutation and duplication within the
gene have been identified in patients with the autosomal dominant
neuropathy, hereditary neuralgic amyotrophy (HNA) [83,93,94]. It
should be pointed out that the role of septin phosphorylation in these
neuronal disorders has not been adequately investigated.
Conclusion
The literature reviewed above links septins to several
neurodegenerative disorders including AD. Although a few studies,
as we have seen, implicate septins in neurodegeneration, a correlation
between septin phosphorylation and pathology, as is the case for tau,
another cytoskeletal protein, has not been reported. Nevertheless, in
view of the well established role of abnormally hyperactivated Cdk5/
p25 in AD and ALS [95,22], it is not inappropriate to speculate that
in disorders in which Cdk5 or other proline directed kinases are
abnormally activated, several septin target substrates located at
the synapse, are abnormally phosphorylated, contributing to the
pathological phenotype. Considering the high incidence of proline
directed consensus sequences in the various human septin families
(Table 1), it is not unlikely that they are targeted for phosphorylation
in neuronal disorders. The defects may manifest themselves not as
tangles, nor plaques, but as more subtle synaptic malfunctions leading
to defects in motor behavior, memory and learning. Those few studies
focused on septin phosphorylation by Cdk5 [76,78] have identified
dramatic effects on synaptic function and should stimulate a more
intensive exploration of the relationship between hyperactive Cdk5/
p25 and septins in various neurodegenerative disorders.
Acknowledgement
The intramural research program of National Institutes of Neurological
Disorders and Stroke, National Institutes of Health supported this work.
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Citation: Amin ND, Grant P, Zheng Y, Kesavapany S, Pant HC (2012) Septin Phosphorylation and Neuronal Degeneration; Role of Cyclin Dependent
Kinase 5 (Cdk5). Brain Disorders Ther S1:002. doi:10.4172/2168-975X.S1-002
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Brain Disorders Ther
Cdk5 and Brain Disorders
ISSN: BDT, an open access journal
Citation: Amin ND, Grant P, Zheng Y, Kesavapany S, Pant HC (2012) Septin Phosphorylation and Neuronal Degeneration; Role of Cyclin Dependent
Kinase 5 (Cdk5). Brain Disorders Ther S1:002. doi:10.4172/2168-975X.S1-002
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This article was originally published in a special issue, Cdk5 and Brain
Disorders handled by Editor(s). Dr. Jyotshnabala Kanungo, National Center
for Toxicological Research, USA
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