ALS mouse model SOD1^G93Adisplays early pathology of sensory small fibers associated to accumulation of a neurotoxic splice variant of peripherin

Abstract

Growing evidence suggests that amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disease that primarily affects motor neurons and, though less evidently, other neuronal systems. About 75% of sporadic and familial ALS patients show a subclinical degeneration of small-diameter fibers, as measured by loss of intraepidermal nerve fibers (IENFs), but the underlying biological causes are unknown. Small-diameter fibers are derived from small-diameter sensory neurons, located in dorsal root ganglia (DRG), whose biochemical hallmark is the expression of type III intermediate filament peripherin. We tested here the hypothesis that small-diameter DRG neurons of ALS mouse model SOD1(G93A)suffer from axonal stress and investigated the underlying molecular mechanism. We found that SOD1(G93A)mice display small fiber pathology, as measured by IENF loss, which precedes the onset of the disease. In vitro small-diameter DRG neurons of SOD1(G93A)mice show axonal stress features and accumulation of a peripherin splice variant, named peripherin56, which causes axonal stress through disassembling light and medium neurofilament subunits (NFL and NFM, respectively). Our findings first demonstrate that small-diameter DRG neurons of the ALS mouse model SOD1(G93A)display axonal stress in vitro and in vivo, thus sustaining the hypothesis that the effects of ALS disease spread beyond motor neurons. These results suggest a molecular mechanism for the small fiber pathology found in ALS patients. Finally, our data agree with previous findings, suggesting a key role of peripherin in the ALS pathogenesis, thus highlighting that DRG neurons mirror some dysfunctions found in motor neurons.

Non‐motor involvement in amyotrophic lateral sclerosis: new insight from nerve and vessel analysis in skin biopsy

“…The sparing of the IENF density proximal‐distal gradient in our patients indicates a non–length‐dependent neuropathic process which has been previously associated with a ganglionopathy rather than an axonopathy. The recent demonstration of a trigeminal small fibre loss through in vivo corneal confocal microscopy and the neuropathological evidence of damaged small diameter dorsal root ganglion cells in a G93A SOD1 murine model of ALS appear to be in agreement with this hypothesis. On the other hand there are experimental data in both patients and animal models supporting the hypothesis that the loss of IENF is due to a distal axonopathy.…”

Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations

“…These classes have been linked to a range of anatomical and physiological characteristics, such as cell soma size, presence of cell-specific protein markers, and electrophysiological properties, which can be used for reliable functional identification (26,29). Disparate sensory subtype sensitivities have previously been observed in mouse models of peripheral nerve disease (30,31). To see whether a particular kind of sensory neuron may be preferentially affected by the Gars C201R mutation, we divided the βIII-tubulin + cell bodies into small, medium, and large area neurons based on previously suggested criteria (32).…”

Sensory neuropathy in progressive motor neuronopathy (pmn) mice is associated with defects in microtubule polymerization and axonal transport

“…A recent study in mutant SOD1 G93A mice, the most widely studied ALS mouse model, reported increased expression of the Peripherin isoform p56 in small DRG neurons, leading to an accumulation of non-assembled neurofilaments and a decrease in assembled neurofilaments (58). This may contribute to the degeneration of small DRG neurons and the loss of sensory axon endings in skin (58). Whether cytoskeletal defects also underlie the degeneration of large sensory axons (24,78) or dorsal root axons (18) remains to be determined.…”