Dysfunction of the oligodendrocytes in amyotrophic lateral sclerosis
Zhenxiang Gong, Li Ba, Min Zhang
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by irreversible deterioration of upper and lower motor neurons (MNs). It has been accepted that ALS is not exclusively a motor neuron disorder, its pathological events occurring between neurons and glial cells are concerning. In the past decades, studies on the involvement of glial cells in the pathogenic process of ALS have mostly revolved around astrocytes and microglia. And oligodendrocytes (OLs) have only recently been highlighted. Grey matter demyelination within the motor cortex and proliferation of the oligodendrocyte precursor cells (OPCs) was observed in ALS patients. Furthermore, selective ablation of mutant SOD1 (the dysfunctional superoxide dismutase) from the oligodendrocyte progenitors (NG2<sup>+</sup> cells) after birth significantly delayed disease onset and prolonged the overall survival in ALS mice (SOD1<sup>G37R</sup>). Moreover, specific overexpression of mutant SOD1 (mSOD1) in mature OLs induced demyelination, promoting MNs degeneration and leading to ALS-like cell phenotype in a zebrafish model. In this study, we reviewed the several mechanisms of oligodendrocyte dysfunction involved in the pathological process of myelin damage and motor neuron death during ALS. Particularly, we examined the insufficient local energy supply from OLs to axons, impaired differentiation from OPCs into OLs mediated by oxidative stress damage, and inflammatory injury to the OLs. Since increasing evidence depicts that ALS is not a disease limited to motor neuron damage, exploring the mechanisms by which oligodendrocyte dysfunction is involved in motor neuron death will contribute to a more comprehensive understanding of ALS and identifying potential drug targets.