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J Neurosci. 2017 Oct 18;37(42):10185-10199. doi: 10.1523/JNEUROSCI.1378-17.2017. Epub 2017 Sep 20.

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

Author information

1
The Miami Project To Cure Paralysis, Leonard M. Miller School of Medicine, University of Miami, Florida 33136.
2
Department Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
3
Department Neurology, University of Miami Miller School of Medicine, Miami, Florida 33136.
4
The Neuroscience Program, University of Miami Miller School of Medicine, Miami, Florida 33136.
5
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida 33136, and.
6
Department Neuropsychiatry, Keio University School of Medicine, Tokyo 160-8582, Japan.
7
The Miami Project To Cure Paralysis, Leonard M. Miller School of Medicine, University of Miami, Florida 33136, r.brambilla@miami.edu.

Abstract

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.SIGNIFICANCE STATEMENT In this study, we show that oligodendrocyte-specific mitochondrial DNA double-strand breaks in PLP:mtPstI mice cause oligodendrocyte death and demyelination associated with axonal damage and glial activation. Hence, PLP:mtPstI mice represent a unique tool to study the pathological consequences of mitochondrial dysfunction in oligodendrocytes, as well as an ideal platform to test remyelinating and neuroprotective agents.

KEYWORDS:

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

PMID:
28931570
PMCID:
PMC5647772
DOI:
10.1523/JNEUROSCI.1378-17.2017
[Indexed for MEDLINE]
Free PMC Article

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