Myelin degeneration induced by mutant superoxide dismutase 1 accumulation promotes amyotrophic lateral sclerosis

Abstract

Myelin is a specialized membrane that wraps around nerve fibers and is essential for normal axonal conduction in neurons. In the central nervous system, oligodendrocytes are responsible for myelin formation. Recent studies have reported pathological abnormalities in oligodendrocytes in human patients with amyotrophic lateral sclerosis (ALS) and a mouse model of ALS expressing the G93A mutation of the human superoxide dismutase 1 (mtSOD1). However, it is unclear whether oligodendrocyte pathology in ALS represents the primary dysfunction induced by mtSOD1 and how mtSOD1 contributes to oligodendrocyte degeneration and ALS pathogenesis. We analyzed GAL4‐VP16‐UAS transgenic zebrafish selectively expressing mtSOD1 in mature oligodendrocytes. We observed that mtSOD1 directly induced oligodendrocyte degeneration by disrupting the myelin sheath and downregulating monocarboxylate transporter 1 (MCT1), thereby causing spinal motor neuron degeneration. Pathological changes observed in this transgenic zebrafish were similar to the pathology observed in the SOD1G93A mouse model of ALS, which is characterized by expression of mtSOD1 in all cells. In addition, oligodendrocyte dysfunction induced by mtSOD1 was associated with anxiety‐related behavioral abnormalities, learning impairments, and motor defects in the early symptomatic stage. We also found that treatment with potassium channel inhibitors rescued behavioral abnormalities without rescuing MCT1 expression, suggesting that myelin disruption induces behavioral abnormalities independently of MCT1. These results indicate that mtSOD1‐induced dysfunction of mature oligodendrocytes is sufficient to induce motor neuron degeneration, thus informing future therapeutic strategies targeted at oligodendrocytes in ALS.

Abnormal Upregulation of GPR17 Receptor Contributes to Oligodendrocyte Dysfunction in SOD1 G93A Mice

“…However, despite this rapid reaction of the GPR17 + pool of precursors, these cells fail to properly maturate at late disease stages, as confirmed by the reduction of the number of mature CC1 + oligodendrocytes. Recently, mutant SOD1 expression in mature oligodendrocytes has been demonstrated to be sufficient to induce myelin defects driving MN degeneration [15]. On this basis, we speculate that GPR17 upregulation starts very early as a positive event to promote substitution of dysfunctional oligodendrocytes.…”

“…Globally, the findings of our in vivo studies suggest that, during disease progression, oligodendrocytes exhibit alterations before disease onset in SOD1 G93A mice. Importantly, these early defects in oligodendrocytes may be linked to myelin abnormalities that have been previously observed prior to symptoms onset in both zebrafish [15] and murine mutant SOD1 models [54], thus contributing to progressive axonal loss. On this basis, restoring the proper OPC differentiation capability may help to preserve MN functionality and to counteract their degeneration.…”

“…Recent studies have demonstrated that also oligodendrocytes, the highly specialized post-mitotic cells that provide trophic and structural support to neurons in both GM and WM of the central nervous system (CNS) [10,11], are severely affected by the presence of mutated SOD1 and contribute to ALS pathogenesis [12][13][14][15]. A precocious and progressive degeneration of oligodendrocytes, together with alterations in myelin structure, have been found in the ventral GM of the spinal cord of both ALS patients and SOD1 G93A mouse model of the disease.…”

Neuron-Oligodendrocyte Interactions in the Structure and Integrity of Axons

“…Animal models with mutant Sod1, which recapitulate the motor neuron loss observed in ALS, have increased oligodendrocyte loss coupled with a failure of new oligodendrocytes to mature (Kang et al, 2013;Philips et al, 2013). In zebrafish models this precedes motor neuron degeneration, suggesting myelin and oligodendrocyte dysfunction is an early pathology in ALS (Kim et al, 2019). Knockout of mutant Sod1 from OPCs delays motor decline and increases survival time, possibly by restoring oligodendrocyte support to the neuron (Lee et al, 2012;Kang et al, 2013).…”

Novel therapeutic targets for amyotrophic lateral sclerosis: ribonucleoproteins and cellular autonomy

“…Oligodendrocytes support axons of MNs partially through the transport of lactate, however the lactate transporter MCT1 in oligodendrocytes is reduced in ALS and associates with axon damage and neuron loss in mouse models and patients [177]. In a zebrafish model, selectively expressing mutant SOD1 in mature oligodendrocytes induced disruption of myelin sheath and downregulation of MCT1, which resulted in MN degeneration [178]. In a human coculture system, oligodendrocytes derived from familial and sporadic ALS patient-derived iPSCs induced MN hyperexcitability and death, while early downregulation of the misfolded SOD1 in progenitor cells resulted in MN rescue in all ALS cases (except for those carrying C9ORF72 repeat expansions) [179].…”