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

Abstract

Global, age-dependent changes in gene expression from rodent models of inherited ALS caused by dominant mutations in superoxide-dismutase 1 (SOD1) were identified by using gene arrays and RNAs isolated from purified embryonic and adult motor neurons. Comparison of embryonic motor neurons expressing a dismutase active ALS-linked mutant SOD1 with those expressing comparable levels of wild-type SOD1 revealed the absence of mutant-induced mRNA changes. An age-dependent mRNA change that developed presymptomatically in adult motor neurons collected by laser microdissection from mice expressing dismutase active ALS-linked mutants was dysregulation of the D/L-serine biosynthetic pathway, previously linked to both excitotoxic and neurotrophic effects. An unexpected dysregulation common to motor neurons expressing either dismutase active or inactive mutants was induction of neuronally derived components of the classic complement system and the regenerative/injury response. Alteration of these mutant SOD1-induced pathways identified a set of targets for therapies for inherited ALS.amyotrophic lateral sclerosis ͉ gene expression profile ͉ laser microdissection A myotrophic lateral sclerosis (ALS) is a fatal, adult-onset neurodegenerative disease that selectively kills brain and spinal cord motor neurons (reviewed in ref. 1). Although most ALS cases are sporadic and of unknown origin, some familial instances are caused by acquired toxic properties of dominant missense point mutations in the ubiquitously expressed superoxide dismutase 1 (SOD1) independent of its dismutase activity (2, 3). Because both familial and sporadic forms lead to what is nearly indistinguishable diseases, the analysis of mutant (human or mouse) SOD1-overexpressing rodent ALS models, which develop a fatal, late-onset, progressive ALS-like paralysis (4-7), can provide valuable tools for dissecting the overall ALS disease mechanism.The central question in understanding ALS in mutant SOD1-expressing mouse and rat models is what are the slowly acting toxic mechanisms, or build-up of toxic products that are responsible for ultimately leading to the degeneration of the most at-risk cell type, the large spinal cord motor neurons (1). Such properties of mutant SOD1 seem likely to induce responses in the genes expressed by motor neurons (their transcriptome) at early disease stages or even before obvious clinical symptoms. Identifying the manner in which motor neurons respond to, or are affected by, ALS-linked mutant SOD1-induced damage could provide key insights either into primary mechanisms of toxicity or to potential therapeutic approaches that may be successful in slowing disease progression in ALS.High-density oligonucleotide microarrays provide an excellent tool to test on a genome wide level the effects of candidate events on the cellular expression profile. Because certain aspects of ALS are non-cell autonomous and originate from mutant SOD1 accumulation in non-motor neuronal cells (8, 9), cell-type specificity is of high importance when using such an a...

d -Amino acid oxidase controls motoneuron degeneration through d -serine

“…Although the L-serine level was also increased (Fig. 3C) consistent with a previous report (20), the D-/L-serine ratio was still higher in mSOD1 mice than in control mice (Fig. 3D).…”

Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase

“…Glutamate action at AMPA receptors also induces SR and D-serine release from astrocytes (25). Interestingly, enzymes involved in D/L serine metabolism (e.g., phosphoserine phosphatase and 3-phosphoglycerate dehydrogenase) are among the earliest transcriptional changes detected in motor neurons in the G37R SOD1 mouse (26).…”

“…Values are means ± SEM. 3.7 who is heterozygous for the R199W mutation, using a peroxidase coupled method modified from Nagata et al (26). A rat spinal cord sample was also assayed in parallel.…”

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

“…An increase in GM3 may also potentially slow disease by promoting oligodendrocyte differentiation (6), which is adversely affected in ALS mice (37), or by inhibiting the activation of matrix metalloproteinase-9 (38), which is expressed at high levels in those MNs most vulnerable in ALS (39). Interestingly, gene expression analysis studies carried out in ALS mice have shown that HEX (an enzyme that metabolizes GM2 to GM3) mRNA level is up-regulated in MNs before and during overt signs of disease (21,22). We confirmed these observations (SI Appendix, Fig.…”

“…Last, patients with adultonset Tay-Sachs disease (GM2 gangliosidosis), a disease triggered by a deficiency in hexosaminidase (HEX), a lysosomal enzyme that hydrolyzes GM2 to GM3, have been reported in some instances to display a disease phenotype that closely mimics ALS (18)(19)(20). Interestingly, HEX mRNA is up-regulated within MNs of transgenic mice expressing the mutant human SOD1 protein (i.e., SOD1 G93A mice), a familial model of ALS (21,22). Collectively, these findings suggest that titration of GSLs is important to maintaining neuromuscular system homeostasis.…”