Altered axonal architecture by removal of the heavily phosphorylated neurofilament tail domains strongly slows superoxide dismutase 1 mutant-mediated ALS

Abstract

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.axonal transport ͉ axonal cytoskeleton ͉ cyclin-dependent kinase 5

Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons

“…Transgenic human SOD1-expressing mice, wild-type SOD1 WT , line 76 (6), mutant SOD1 G37R , line 42 (6) and mutant SOD1 G85R , line 148 (5), were on a pure C57BL/6 genetic background, whereas transgenic human SOD1-expressing rats, wildtype SOD1 WT (45) and mutant SOD1 G93A (7), were on a SpragueDawley genetic background. Genotyping was performed as described (46). Embryonic Rat Motor Neurons.…”

α-Internexin Is Structurally and Functionally Associated with the Neurofilament Triplet Proteins in the Mature CNS

“…In exceptional cases, such as mature cerebellar granules cells, ␣-internexin is reported to exist in the absence of detectable neurofilament triplet (Chien et al, 1996). In contrast, the concept of the neurofilament as a polymer composed of three subunits continues to be universally accepted and consistently articulated, without exception, in all published works and major reviews on this subject (Perrone Capano et al, 2001;Al-Chalabi and Miller, 2003;Gama Sosa et al, 2003;Garcia et al, 2003;Xia et al, 2003;Cairns et al, 2004a;Lariviere and Julien, 2004;Liu et al, 2004;Lobsiger et al, 2005;Petzold, 2005;Theiss et al, 2005). The physiological roles of ␣-internexin, therefore, remain essentially undefined.…”

Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice

“…Motor neuron disease from expression of mutant SOD1 has previously been demonstrated to arise from loss of the pool of large caliber motor axons (21), including for end-stage mutant SOD1 G37R (22) (see also Fig. 3 A and E).…”