ABSENCE OF NEUROFILAMENTS REDUCES THE SELECTIVE VULNERABILITY OF MOTOR-NEURONS AND SLOWS DISEASE CAUSED BY A FAMILIAL AMYOTROPHIC LATERAL SCLEROSIS-LINKED SUPEROXIDE-DISMUTASE-1 MUTANT

Mutations in superoxide dismutase 1 (SOD1), the only proven cause of a myotrophic lateral sclerosis (ALS), provoke disease through an unident ified toxic property. Neurofilament aggregates are pathologic hallmark s of both sporadic and SOD1-mediated familial ALS, By deleting NF-L, t he major neurofilament subunit required for filament assembly, onset a nd progression of disease caused by familial ALS-linked SOD1 mutant G8 5R are significantly slowed, while selectivity of mutant-mediated toxi city for motor neurons is reduced. In NF-L-deleted animals, levels of the two remaining neurofilament subunits, NF-M and NF-H, are markedly reduced in axone but are elevated in motor neuron cell bodies. Thus, w hile neither perikaryal nor axonal neurofilaments are essential for SO D1-mediated disease, the absence of assembled neurofilaments both dimi nishes selective vulnerability and slows SOD1(G85R) mutant-mediated to xicity to motor neurons.