(Read Only) Julien_US_Neuro 16/02/2010 10:15 Page 33
Maldistribution of Neurofilaments, Disease Pathogenesis, and Amyotrophic Lateral Sclerosis
rescued by overexpression of hNFL in a dosage-dependent fashion.
35
Alternatively, such apparent discrepancies may reflect the existence
Overexpression of peripherin provokes late-onset motor neuron of multiple neuroprotection mechanisms. It is noteworthy that hNFH
degeneration in transgenic mice.
36,37
The motor neuron loss is preceded overexpression conferred more robust protective effects than
by axonal transport defects and formation of axonal spheroids.
38
deletion of NF sidearms, with lifespan extension of six months
Interestingly, NFH overexpression abolished the formation of axonal compared with two months in the SOD1
G37R
mice.
39,43
The superior
spheroids that might block transport. These findings illustrate the protective effects of hNFH overexpression could have resulted from
importance of IF protein stoichiometry in the formation, distribution, depletion of axonal NF content together with phosphorylation sink of
and toxicity of neuronal IF inclusions. perikaryal NF accumulations. Finally, Ehlers et al.
53
have shown that
NFs are involved in localisation of NMDA receptors in the neuronal
In ALS, there is a 70% decrease in levels of NFL mRNA observed in plasma membrane by interacting with the NMDA NR1 sub-unit,
degenerating motor neurons.
4
This could be due in part to suggesting that accumulation of NFs may interfere with glutamate
modification in the stability of their mRNA. Ge et al.
39
have shown that receptor function. There is a report that NF-aggregate-bearing
ALS-linked SOD1 mutant proteins bind to and destabilize NFL mRNA neurons exhibit increased intracellular calcium levels and enhanced
whereas normal SOD1 does not. Moreover, 14-3-3 and trace amine cell death in response to NMDA-mediated excitotoxicity.
54
receptor (TAR) DNA-binding protein 43 (TDP-43) are two proteins
incorporated in ALS intraneuronal aggregates that bind and Conclusion
destabilize NFL mRNA,
40,41
a phenomenon that could contribute to the Accumulation of NFs in ALS was described for the first time several
aggregation of NFs in ALS. decades ago. Nevertheless, how the NF accumulations arise and the
extent to which they contribute to disease pathogenesis is not fully
Mouse Models with Neurofilament Abnormalities elucidated. Lines of evidence suggest that perturbations of axonal
In the last two decades, the gene-targeting technique and transgenic transport or of IF protein stoichiometry can contribute to formation of
mouse approaches have been used to investigate the contribution of intraneuronal IF inclusions, these two mechanisms not being mutually
cytoskeletal abnormalities in ALS pathogenesis (see Table 2). exclusive. Alterations in the stoichiometry of IF proteins can result
Evidence that NF disorganization in vivo can provoke neuronal death from destabilization of IF mRNAs. Aberrant phosphorylation of NFs
came from the observation that expression of a mutated NFL protein
42
can also affect their axonal transport, but this phenomenon is poorly
or of an excess of peripherin
36
in transgenic mice induced the understood. A regulation of NF interactions to molecular motors is
formation of ALS-like NF aggregates and selective degeneration of most probably involved in controlling NF movement. In order to
spinal motor neurons. develop a therapeutic approach able to restore a normal axonal
transport of NFs in ALS, it will be important to identify which
Abnormal NF accumulations have been detected in familial ALS cases molecular motors and adaptor proteins are involved in this process.
due to SOD1 mutations.
43
Similarly, transgenic mice expressing In mouse models, some types of NF accumulation correlate with
mutant SOD1 exhibit NF accumulations
44,45
and defective axonal motor neuron degeneration, whereas others seem to confer
transport of NFs in motor neurons.
20,21
To determine whether axonal protection. The toxicity or benefit of NF accumulations could be due
NFs are involved in SOD1-mediated disease, mice expressing mutant to differences in their localization (perikaryal versus axonal) and their
SOD1 were mated with mice having low axonal NF content.
46,47
The ability to block fast axonal transport and sequestrate other vital
results indicated that axonal NFs are not required for SOD1-mediated organelles, such as mitochondria. n
disease. Nonetheless, the absence of NFL in SOD1
G85R
caused
depletion of axonal NFs and extension of lifespan by approximately
Rodolphe Perrot, PhD, is a Post-doctoral Fellow in the
15%.
46
Surprisingly, overexpression of hNFH in SOD1
G37R
mice
47
and of
Department of Anatomy and Physiology at the Research
mouse NFL or mouse NFH in SOD1
G93A
mice
48
also increased their
Center at Laval University Hospital Center in Québec. His
lifespan by 65 and 15%, respectively. However, the mechanism of
research focuses on investigating the pathogenic
mechanisms associated with disorganization of the
protection is still unclear. NF proteins contain multiple calcium
neuronal cytoskeleton. He obtained his PhD in
binding sites.
49
molecular and cellular biology in 2006 at the Laboratory
of Neurobiology and Transgenesis at Angers University
Hospital in France.
Therefore there is a possibility that perikaryal accumulations of NF
proteins may act as calcium chelators to confer neuroprotection in a
Jean-Pierre Julien, PhD, is a Professor and holds a
manner reminiscent of the calcium-binding protein calbindin-D28k
Canada Research Chair in the Department of Anatomy
when overexpressed in cultured motor neurons.
50
Nguyen et al.
51
also
and Physiology at the Research Center at Laval
proposed that perikaryal accumulations of NFs in motor neurons may
University Hospital Center. Prior to this, he was a
Professor at McGill University. His studies with
alleviate ALS pathogenesis by acting as a phosphorylation sink for
genetically modified mice led to the first demonstration
cyclin-dependent kinase 5 (CDK5) dysregulation induced by mutant
that disorganization of intermediate filaments may
SOD1, thereby reducing the detrimental hyperphosphorylation of
cause neurological disease. In 2000, Professor Julien
received the Sheila Essey Award for research on
tau and other neuronal substrates. However, this hypothesis has
amyotrophic lateral sclerosis (ALS) from the American Academy of Neurology (AAN).
been challenged because removal of NFM and NFH sidearms also led
He obtained his PhD from McGill University and carried out post-doctoral work at the
to a delay of disease in SOD1 mutant mice,
52
probably through
National Institute for Medical Research (NIMR) in the UK.
enhancement of anterograde axonal transport.
US NEUROLOGY 33
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