Brain 2014: 137; 646–653
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BRAIN
A JOURNAL OF NEUROLOGY
SCIENTIFIC COMMENTARIES
Lafora’s odyssey reaches a mysterious port of call
In 1911, the Spanish neurologist-pathologist Gonzalo Lafora,
working at the then Government Hospital for the Insane in
Washington DC, first described the progressive myoclonus epilepsy that would later bear his name (Lafora, 1911). The journey
to understand this disease started with Lafora’s detailed neuropathological description of the large and profuse inclusions
(Fig. 1) that would come to be known as Lafora bodies. The
odyssey has visited many a shore, and the latest and most mysterious is revealed by Javier Gayarre et al. (2014) in this issue of
Brain.
Whereas the ‘amyloid’ plaques of Alzheimer’s disease are not in
fact amyloid (starch), Lafora bodies, by contrast, are. Lafora
bodies are composed of hyperphosphorylated and malformed
glycogen molecules. These abnormal starch-like polyglucosans
aggregate to form insoluble masses, which over time accumulate
inside neuronal somata and dendrites.
Lafora disease is caused by loss-of-function mutations in the
EPM2A (laforin) or EPM2B (malin) genes (Minassian et al.,
1998; Chan et al., 2003). Laforin is the only known glycogen
phosphatase. Its absence leads to hyperphosphorylation of glycogen, which correlates with a gradual accumulation of polyglucosans, strongly suggesting that glycogen hyperphosphorylation
underlies polyglucosan formation (Tagliabracci et al., 2008).
Laforin’s structure resembles that of the plant starch phosphatase
SEX4, which is crucial to starch metabolism; its absence leading to
a pathological excess of starch. Laforin complements SEX4 and
rescues the starch-excess phenotype of SEX4-deficient plants
(Gentry et al., 2007). The phosphatase activity of laforin is its
only known enzymatic function. Together, these findings suggest
a central role for impaired glycogen dephosphorylation by laforin
in Lafora disease pathogenesis. As for the enzyme behind glycogen phosphorylation, despite many efforts to identify it, that shore
remains unattained.
Malin, meanwhile, has been shown to be a ubiquitin E3 ligase.
Paradoxically, malin’s only unequivocal target for proteasomal
degradation turns out to be none other than laforin (Gentry
et al., 2005). How can the absence of malin lead to the same
disease as does absence of the protein, laforin, that malin destroys? A solution to this conundrum was suggested by recent
work which revealed that, in the absence of malin, laforin
accumulates in glycogen and may thus disturb the spherical architecture that is essential for glycogen’s solubility (Tiberia et al.,
2012). As such, excess phosphate in glycogen (as a result of
laforin deficiency) or excess laforin in glycogen (due to malin deficiency) would have the same effect on glycogen, reducing its
solubility and leading it to precipitate and form Lafora bodies.
In the current issue of Brain, Gayarre et al. (2014) guide the
ship into a new night. They overexpress, in laforin-deficient mice,
a form of laforin mutated to lack phosphatase activity, and show
that this rescues murine Lafora disease. The inescapable conclusion
is that the phosphatase function of laforin is dispensable, and that
it is some other function of the laforin-malin complex that is relevant to the disease. The function that Gayarre et al. (2014) highlight, namely autophagy, has been of late a frequent stop in the
Lafora voyage, and indeed in the exploration of many other neurodegenerative diseases. Autophagy is disturbed in Lafora disease
(Criado et al., 2012), and it has been suggested that defective
autophagy impairs the ability of cells to rid themselves of abnormal aggregates, such as malformed glycogen. Gayarre et al.
(2014) advance the tantalizing idea that glycogen, in common
with proteins, can sometimes be naturally misshapen. This
would lead it to precipitate and aggregate, and indeed to accumulate were it not for mechanisms involving laforin and malin
that act to clear such deposits. Before accepting autophagy as a
port of call of the Lafora saga, one must however keep an open
mind. Is it possible that laforin’s sole enzymatic activity is
unnecessary?
The vicissitudes of the Lafora epic will certainly continue to lead
us to exciting lands of milk and honey most relevant to the understanding of neuronal function. But what of the patients who suffer
the intractable and continuous seizures, hallucinations and dementia of Lafora disease? The polyglucosans that cause havoc in
Lafora disease, irrespective of their shape or origins, are in the
end nothing more than chains of glucose. One and only one
enzyme, glycogen synthase, manufactures chains of glucose, and
recent studies have shown that downregulation of glycogen synthesis prevents Lafora disease in mice (Pederson et al., 2014).
While the Lafora pathogenesis ship feels its way through the unknown, a shortcut to safe harbour, namely glycogen synthesis
downregulation, may well be open for patients with the disease.
ß The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: [email protected]
Scientific Commentaries
Figure 1 Lafora bodies as drawn by Lafora in his original manuscript (Lafora, 1911).
Brain 2014: 137; 646–653
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| Brain 2014: 137; 646–653
Gonzalo Lafora would have appreciated the progress made by the
explorers so far.
Berge A. Minassian
Division of Neurology,
Department of Paediatrics, and Program in
Genetics and Genome Biology,
The Hospital for Sick Children,
Toronto Canada,
Institute of Medical Sciences,
University of Toronto,
University of Toronto Michael Bahen Chair in Epilepsy Research
Correspondence to: Berge A. Minassian
E-mail: [email protected]
doi:10.1093/brain/awu018
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Scientific Commentaries
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Removing the brakes on post-stroke plasticity
drives recovery from the intact hemisphere
and spinal cord
The existence of bilaterally redundant corticospinal pathways suggests a potential means of recovery after unilateral injury such as
stroke. However, in the adult brain, plasticity is kept in check by
inhibitory factors that provide the stability necessary in neuronal
networks to encode memories and retain learned actions. In the
current issue of Brain, Nicolas Lindau and colleagues use antibodies that block Nogo-A functioning to unlock plasticity within the
adult injured brain, leading to a structural and functional re-routing of corticospinal signals to exploit circuit redundancy (Lindau
et al., 2014).
After a large motor cortex stroke, there is evidence that the
intact hemisphere can control the impaired hand and thus facilitate
behavioural recovery (Grefkes and Ward, 2014). However, hemiparesis remains a common deficit after stroke, indicating a need
for therapies that augment spontaneous recovery. Lindau et al.
(2014) show that, in rats, promoting axonal sprouting by blocking
the growth-inhibitor protein Nogo-A facilitates the emergence of
motor pathways that allow the intact hemisphere to drive motor
output to the impaired forelimb. Although only 10% of corticospinal projections terminated in the ipsilateral spinal cord before
injury, anti-Nogo-A therapy induced the generation of additional
ipsilateral motor projections and produced substantial recovery of
forelimb function.
During the development and refinement of the nervous system
there is extensive axonal sprouting. To curb ebullient outgrowth in
the adult, various inhibitory molecules such as Nogo-A keep the
system in check. Over the years, the Schwab group has systematically examined the therapeutic potential of inhibiting Nogo-A in
a number of disease models, including stroke. Initial efforts were
aimed at enhancing sprouting at the cortical level through the
expression of Nogo-A antibodies in peri-infarct tissue (Emerick
et al., 2003). To evaluate a more clinically accessible approach
to treatment, Lindau et al. (2014) delivered a Nogo-A inhibitor
intrathecally to the lumbar spinal cord. This method builds on