Altered axonal architecture by removal of the heavily phosphorylated neurofilament tail domains strongly slows superoxide dismutase 1 mutant-mediated ALS.
Eliminating assembled neurofilaments (NFs) from axons or misaccumulating NFs in motor neuron cell bodies strongly slows disease in mouse models of mutant superoxide dismutase 1 (SOD1)-induced amyotrophic lateral sclerosis. One proposal for how reducing axonal NFs can increase survival is that the multiphosphorylated tail domains of the two larger NF subunits act in motor neuron cell bodies as phosphorylation sinks where they mitigate cyclin-dependent kinase 5 dysregulation induced by mutant SOD1. Elimination by gene targeting in mice of the NF medium and NF heavy tail domains and their 58 known phosphorylation sites accelerates aberrant phosphorylation of other neuronal substrates while leaving overall NF content unaltered. However, disease onset is significantly delayed and survival is extended, inconsistent with the ameliorative property of altered NF content protecting by serving as substrates for dysregulation of any NF kinase. Moreover, at comparable disease stages significantly more surviving motor neurons and axons were found in SOD1 mutant mice deleted in the NF tails than in similar mice with wild-type NFs. This finding supports noncell autonomous toxicity in SOD1 mutant-mediated amyotrophic lateral sclerosis: removal of the NF tails slows damage developed directly within motor neurons, but SOD1 mutant damage within nonneuronal supporting cells reduces motor neuron functionality.
Ludwig Institute for Cancer Research and Department of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Christian S
CS
Lobsiger
Michael L
ML
Garcia
Christopher M
CM
Ward
Don W
DW
Cleveland
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D018390:Gene Targeting; D015151:Immunoblotting; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D016900:Neurofilament Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
D016900:Neurofilament Proteins; C051774:neurofilament protein H; C061195:neurofilament protein M; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D018844:Cyclin-Dependent Kinases