Oligodendrocyte dysfunction in the pathogenesis of amyotrophic lateral sclerosis

• Published in: Brain (London, England : 1878) Vol. 136; no. Pt 2; pp. 471 - 482
• Main Authors: Philips, Thomas, Bento-Abreu, Andre, Nonneman, Annelies, Haeck, Wanda, Staats, Kim, Geelen, Veerle, Hersmus, Nicole, Küsters, Benno, Van Den Bosch, Ludo, Van Damme, Philip, Richardson, William D, Robberecht, Wim
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.02.2013
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - enzymology; Amyotrophic Lateral Sclerosis - pathology; Amyotrophic Lateral Sclerosis - physiopathology; Animal models; Animals; Cell Line, Tumor; Cell Proliferation; Data processing; Differentiation; Disease Models, Animal; Genes, Reporter; Glial stem cells; Humans; Infectious diseases; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor neurons; Myelin basic protein; Neurodegeneration; Neurodegenerative diseases; Oligodendrocytes; Oligodendroglia - enzymology; Oligodendroglia - pathology; Original; Protein transport; Spinal cord; Stem cells; Substantia grisea; Superoxide dismutase; Superoxide Dismutase - genetics
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/aws339

Oligodendrocytes are well known targets for immune-mediated and infectious diseases, and have been suggested to play a role in neurodegeneration. Here, we report the involvement of oligodendrocytes and their progenitor cells in the ventral grey matter of the spinal cord in amyotrophic lateral sclerosis, a neurodegenerative disease of motor neurons. Degenerative changes in oligodendrocytes were abundantly present in human patients with amyotrophic lateral sclerosis and in an amyotrophic lateral sclerosis mouse model. In the mouse model, morphological changes in grey matter oligodendrocytes became apparent before disease onset, increasingly so during disease progression, and oligodendrocytes ultimately died. This loss was compensated by increased proliferation and differentiation of oligodendrocyte precursor cells. However, these newly differentiated oligodendrocytes were dysfunctional as suggested by their reduced myelin basic protein and monocarboxylate transporter 1 expression. Mutant superoxide dismutase 1 was found to directly affect monocarboxylate transporter 1 protein expression. Our data suggest that oligodendroglial dysfunction may be a contributor to motor neuron degeneration in amyotrophic lateral sclerosis.