Mitochondrial DNA Double-Strand Breaks in Oligodendrocytes Cause Demyelination, Axonal Injury, and CNS Inflammation

作者：Madsen Pernille M; Pinto Milena; Patel Shreyans; McCarthy Stephanie; Gao Han; Taherian Mehran; Karmally Shaffiat; Pereira Claudia V; Dvoriantchikova Galina; Ivanov Dmitry; Tanaka Kenji F; Moraes Carlos T; Brambilla Roberta^*

来源：Journal of Neuroscience, 2017, 37(42): 10185-10199.

DOI：10.1523/JNEUROSCI.1378-17.2017

• animal model
• demyelination
• mitochondria
• multiple sclerosis
• oxidative phosphorylation
• remyelination

Mitochondrial dysfunction has been implicated in the pathophysiology of neurodegenerative disorders, including multiple sclerosis (MS). To date, the investigation of mitochondrial dysfunction in MS has focused exclusively on neurons, with no studies exploring whether dysregulation of mitochondrial bioenergetics and/or genetics in oligodendrocytes might be associated with the etiopathogenesis of MS and other demyelinating syndromes. To address this question, we established a mouse model where mitochondrial DNA(mtDNA) double-strand breaks (DSBs) were specifically induced in myelinating oligodendrocytes (PLP:mtPstI mice) by expressing a mitochondrial-targeted endonuclease, mtPstI, starting at 3 weeks of age. In both female and male mice, DSBs of oligodendroglial mtDNA caused impairment of locomotor function, chronic demyelination, glial activation, and axonal degeneration, which became more severe with time of induction. In addition, after short transient induction of mtDNA DSBs, PLP:mtPstI mice showed an exacerbated response to experimental autoimmune encephalomyelitis. Together, our data demonstrate that mtDNA damage can cause primary oligodendropathy, which in turn triggers demyelination, proving PLP:mtPstI mice to be a useful tool to study the pathological consequences of mitochondrial dysfunction in oligodendrocytes. In addition, the demyelination and axonal loss displayed by PLP:mtPstI mice recapitulate some of the key features of chronic demyelinating syndromes, including progressive MS forms, which are not accurately reproduced in the models currently available. For this reason, the PLP: mtPstI mouse represents a unique and much needed platform for testing remyelinating therapies.

• 出版日期2017-10-18