What Is the Role of Oligodendrocytes in Amyotrophic Lateral Sclerosis?

Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons in the cerebral cortex, brainstem, and spinal cord. There is growing evidence that astrocytes, microglia, and oligodendrocytes participate in the pathodynamics of ALS via both loss-of-function and toxic gain-of-function mechanisms.¹ Whereas most studies have focused on the role of microglia and astrocytes,^1,2 oligodendrocytes may also have a major pathogenic role in this disorder^3-6 (Figure). A recent analysis applying a polygenic risk score approach indicated that variation in genes involved in neuronal morphogenesis and membrane trafficking are a major genetic risk for ALS.⁷ This study also showed that subtypes of oligodendrocytes, as well as parvalbumin-expressing GABAergic neurons in the motor cortex, were significantly enriched in ALS risk genes in humans.⁷ Oligodendrocytes are the targets of mutations affecting ALS-related genes and their dysfunction may affect motor neuron survival by several mechanisms. Experimental models of ALS indicate that the inability of oligodendrocyte precursors to fully differentiate into mature oligodendrocytes renders them unable to provide metabolic support and myelinate the axons.^3-6 In vitro co-culture studies show that oligodendrocytes derived from induced pluripotent or neural progenitor cells from patients with familial ALS associated with superoxide dismutase 1 (SOD1) or other mutations, as well as those from patients with sporadic ALS, may also have an active role in motor neuron death via cell-contact mechanisms.⁵ These findings expand the potential cellular targets for neuroprotection in ALS.⁶