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.

Keywords: axonal degeneration; demyelination; oligodendrocyte.

Figure 1

Pathological oligodendrogenesis and myelination in amyotrophic lateral sclerosis (ALS) disease. (A) In the healthy central nervous system (CNS), oligodendrogenesis comprises the differentiation of oligodendrocyte progenitor cells (OPC) into pre-myelinating oligodendrocytes, which mature into myelinating cells. Specific markers of each phenotypic step are indicated. The blue arrow indicates the proliferation of OPCs. (B) Myelination of neuronal axons by oligodendrocytes takes place in the presence of microglial and astroglial cells, which are known to participate namely in the differentiation of OPCs (via the secretion of IGF-1) and the supply of metabolic nutrients (via gap junctions enriched in channel forming proteins connexin, Cx) and lipids for myelin sheath production. (C) During ALS disease, oligodendrogenesis is characterized by the increase of OPC proliferation, which gives rise to a higher number of differentiated oligodendrocytes. The latter are dysmorphic and display various protein aggregates in their cytoplasm including (TDP-43 or ErBB4, SOD1, FUS) or accumulate abnormal dipeptide repeat proteins (C9orf72) in their nucleus. These abnormal oligodendrocytes are unable to mature into myelinating cells and ultimately die. In response to cell death, OPC proliferation is highly increased (red arrow). (D) Cellular and molecular mechanisms involved in ALS pathology include axon demyelination and degeneration that may occur as the primary or secondary event compared to the death of oligodendrocytes. Both glutamate excitotoxicity (orange broken arrow) from the degenerating neurons and the dysregulation of protein folding leading to abnormal aggregates (blue and orange ellipses) lead to endoplasmic reticulum stress resulting into the increase of the ER stress apoptotic mediator CHOP and into the activation of the unfolded protein response (UPR) associated with the specific expression of select UPR target genes, such as PDI (protein disulfide isomerase). At the level of oligodendrocyte processes, the most abundant myelin protein MBP and the monocarboxylate transporter 1 (MCT1) required for lactate release to the axon are both decreased. The altered communication between the oligodendrocyte and the neighboring astrocytes (green) related to changes in connexin (Cx) expression as well as the pro-inflammatory microglia (blue) namely secreting the cytokine TNFα and triggering the RIPK1/RIPK3/MLKL signaling pathway, both participate in oligodendrocyte dysfunction and degeneration, respectively.