Defective Oligodendroglial Lineage and Demyelination in Amyotrophic Lateral Sclerosis

Abstract

Motor neurons and their axons reaching the skeletal muscle have long been considered as the best characterized targets of the degenerative process observed in amyotrophic lateral sclerosis (ALS). However, the involvement of glial cells was also more recently reported. Although oligodendrocytes have been underestimated for a longer time than other cells, they are presently considered as critically involved in axonal injury and also conversely constitute a target for the toxic effects of the degenerative neurons. In the present review, we highlight the recent advances regarding oligodendroglial cell involvement in the pathogenesis of ALS. First, we present the oligodendroglial cells, the process of myelination, and the tight relationship between axons and myelin. The histological abnormalities observed in ALS and animal models of the disease are described, including myelin defects and oligodendroglial accumulation of pathological protein aggregates. Then, we present data that establish the existence of dysfunctional and degenerating oligodendroglial cells, the chain of events resulting in oligodendrocyte degeneration, and the most recent molecular mechanisms supporting oligodendrocyte death and dysfunction. Finally, we review the arguments in support of the primary versus secondary involvement of oligodendrocytes in the disease and discuss the therapeutic perspectives related to oligodendrocyte implication in ALS pathogenesis.

Distinctive whole-brain cell types predict tissue damage patterns in thirteen neurodegenerative conditions

“…In response to oligodendrocyte damage, OPCs initiate their proliferation and differentiation for the purpose of repairing damaged myelin ( Ohtomo et al, 2018 ). In AD, PD, and ALS, the OPCs become unable to differentiate and their numbers decrease, leading to a reduction in myelin production and subsequent neural damage ( Traiffort et al, 2021 ; Spaas et al, 2021 ).…”

Icariin prevents methylmercury-induced experimental neurotoxicity: Evidence from cerebrospinal fluid, blood plasma, brain samples, and in-silico investigations

“…Dysfunctional astrocytes and oligodendrocytes in ALS secrete harmful substances, exacerbating motor neuron loss and myelin damage [ 64 , 65 ]. Demyelination in ALS reduces neuronal connectivity, worsening the disease [ 66 ]. Understanding ALS's mechanisms, including motor neuron degeneration and genetic factors, is crucial.…”

lncRNA Sequencing Reveals Neurodegeneration-associated FUS Mutations Alter Transcriptional Landscape of iPS Cells That Persists In Motor Neurons

“…Overall, our data show that cells carrying FUS mutants show an increase in lnc-GPR149 and in its predicted mRNA target, GPR149. These increases in GPR149 are of particular interest given its contribution to inhibitor interneurons and myelination, as excitotoxicity and myelination defects have been noted in some cases of ALS 73 , 74 . Overall, our findings present a compelling case for further exploration of the role of GPR149 in neurodegeneration.…”