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 amyotrophic lateral sclerosis (ALS), provoke disease through an unidentified toxic property. Neurofilament aggregates are pathologic hallmarks of both sporadic and SOD1-mediated familial ALS. By deleting NF-L, the major neurofilament subunit required for filament assembly, onset and progression of disease caused by familial ALS-linked SOD1 mutant G85R are significantly slowed, while selectivity of mutant-mediated toxicity 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 axons but are elevated in motor neuron cell bodies. Thus, while neither perikaryal nor axonal neurofilaments are essential for SOD1-mediated disease, the absence of assembled neurofilaments both diminishes selective vulnerability and slows SOD1(G85R) mutant-mediated toxicity to motor neurons.
Williamson
T L
TL
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA.
Bruijn
L I
LI
Zhu
Q
Q
Anderson
K L
KL
Anderson
S D
SD
Julien
J P
JP
Cleveland
D W
DW
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001369:Axons / Q000473:pathology; D018450:Disease Progression; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000473:pathology*; D009154:Mutation; D016900:Neurofilament Proteins / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics*
D016900:Neurofilament Proteins; C044882:neurofilament protein L; D013482:Superoxide Dismutase