Cytoskeletal abnormalities in amyotrophic lateral sclerosis: beneficial or detrimental effects?

Cytoskeletal abnormalities have been reported in cases of amyotrophic lateral sclerosis (ALS) including abnormal inclusions containing neurofilaments (NFs) and/or peripherin, reduced mRNA levels for the NF light (NF-L) protein and mutations in the NF heavy (NF-H) gene. Recently, transgenic mouse approaches have been used to address whether cytoskeletal changes may contribute to motor neuron disease. Mice lacking one of the three NF subunits are viable and do not develop motor neuron disease. Nonetheless, mice with null mutations for NF-L or for both NF-M and NF-H genes developed severe atrophy of ventral and dorsal root axons. The atrophic process is associated with hind limb paralysis during aging in mice deficient for both NF-M and NF-H proteins. The overexpression in mice of transgenes coding for wild-type or mutant NF proteins can provoke abnormal NF accumulations, axonal atrophy and sometimes motor dysfunction. However, the perikaryal NF accumulations are generally well tolerated by motor neurons and, except for expression of a mutant NF-L transgene, they did not provoke massive motor neuron death. Increasing the levels of perikaryal NF proteins may even confer protection in motor neuron disease caused by ALS-linked mutations in the superoxide dismutase (SOD1). In contrast, the overexpression of wild-type peripherin, a type of IF gene upregulated by inflammatory cytokines, provoked the formation of toxic IF inclusions with the high-molecular-weight NF proteins resulting in the death of motor neurons during aging. These results together with the detection of peripherin inclusions at early stage of disease in mice expressing mutant SOD1 suggest that IF inclusions containing peripherin may play a contributory role in ALS pathogenesis.