Charcot-Marie-Tooth (CMT) disorders are a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies characterized by muscle weakness and wasting, foot and hand deformities, and electrophysiological changes. The CMT4H subtype is an autosomal recessive demyelinating form of CMT that was recently mapped to a 15.8-Mb region at chromosome 12p11.21-q13.11, in two consanguineous families of Mediterranean origin, by homozygosity mapping. We report here the identification of mutations in FGD4, encoding FGD4 or FRABIN (FGD1-related F-actin binding protein), in both families. FRABIN is a GDP/GTP nucleotide exchange factor (GEF), specific to Cdc42, a member of the Rho family of small guanosine triphosphate (GTP)-binding proteins (Rho GTPases). Rho GTPases play a key role in regulating signal-transduction pathways in eukaryotes. In particular, they have a pivotal role in mediating actin cytoskeleton changes during cell migration, morphogenesis, polarization, and division. Consistent with these reported functions, expression of truncated FRABIN mutants in rat primary motoneurons and rat Schwann cells induced significantly fewer microspikes than expression of wild-type FRABIN. To our knowledge, this is the first report of mutations in a Rho GEF protein being involved in CMT.
The reasons for the cellular specificity and slow progression of motoneuron diseases such as ALS are still poorly understood. We previously described a motoneuron-specific cell death pathway downstream of the Fas death receptor, in which synthesis of nitric oxide (NO) is an obligate step. Motoneurons from ALS model mice expressing mutant SOD1 showed increased susceptibility to exogenous NO as compared with controls. Here, we report a signaling mechanism whereby NO leads to death of mutant, but not control, motoneurons. Unexpectedly, exogenous NO triggers expression of Fas ligand (FasL) in cultured motoneurons. In mutant SOD1 G93A and SOD1 G85R , but not in control motoneurons, this up-regulation results in activation of Fas, leading through Daxx to phosphorylation of p38 and further NO synthesis. This Fas͞NO feedback amplification loop is required for motoneuron death in vitro. In vivo, mutant SOD1 G93A and SOD1 G85R mice show increased numbers of positive motoneurons and Daxx nuclear bodies weeks before disease onset. Moreover, FasL up-regulation is reduced in the presence of transgenic dominant-negative Daxx. We propose that chronic low-level activation of the Fas͞NO feedback loop may underlie the motoneuron loss that characterizes familial ALS and may help to explain its slowly progressive nature.cell death ͉ motoneuron disease ͉ NO ͉ p38 kinase ͉ neurodegeneration A myotrophic lateral sclerosis (ALS) is the most frequent adultonset motoneuron disease in humans. ALS is characterized by the selective degeneration of motoneurons in spinal cord, brainstem, and cerebral cortex leading to muscle atrophy and paralysis and ultimately to death. About 1 to 2% of all human ALS forms are caused by dominantly inherited mutations in the Cu͞Zn superoxide dismutase (SOD1) gene. Mice transgenic for the ALS-linked SOD1 mutations G37R (1), H46R͞H48Q (2), G85R (3), and G93A (4) develop an adult-onset motoneuron disorder that remarkably resembles human ALS.Despite much intensive study, many questions remain concerning the mechanism(s) by which mutant SOD1 triggers specific motoneuron death. One unresolved issue is the cellular site of action of the gain-of-function mutations. Clement et al. (5) generated chimeric mice carrying a mixture of WT and mutant SOD1-expressing cells in the spinal cord. In these mice, WT motoneurons eventually showed stigmata of degeneration, whereas some mutant SOD1 motoneurons were protected from degeneration when surrounded by WT nonneuronal cells. These results suggest that mutant SOD1 in both motoneurons and surrounding cells may play a role in the disease process.Our earlier studies using cultures of purified embryonic motoneurons reached similar conclusions. We found that motoneurons from SOD1 G93A , SOD1 G37R , and SOD1 G85R mice survived normally in the presence of optimal trophic support or when challenged by excitotoxic agonists. In marked contrast, compared with controls, they displayed a 10-to 100-fold increase in sensitivity to extracellular agonists of the Fas receptor or to exogenous nitr...
Indices of neuroinflammation are found in a variety of diseases of the CNS including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Over the years, neuroinflammation, in degenerative disorders of the CNS, has evolved from being regarded as an innocent bystander accomplishing its housekeeping function secondary to neurodegeneration to being considered as a bona fide contributor to the disease process and, in some situations, as a putative initiator of the disease. Herein, we will review not only neuroinflammation in both ALS and SMA from the angle of neuropathology, but also from the angle of its potential role in the pathogenesis and treatment of these two dreadful paralytic disorders.
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