Dataset Information

Attenuating the DNA damage response to double-strand breaks restores function in models of CNS neurodegeneration.

ABSTRACT: DNA double-strand breaks are a feature of many acute and long-term neurological disorders, including neurodegeneration, following neurotrauma and after stroke. Persistent activation of the DNA damage response in response to double-strand breaks contributes to neural dysfunction and pathology as it can force post-mitotic neurons to re-enter the cell cycle leading to senescence or apoptosis. Mature, non-dividing neurons may tolerate low levels of DNA damage, in which case muting the DNA damage response might be neuroprotective. Here, we show that attenuating the DNA damage response by targeting the meiotic recombination 11, Rad50, Nijmegen breakage syndrome 1 complex, which is involved in double-strand break recognition, is neuroprotective in three neurodegeneration models in Drosophila and prevents A?1-42-induced loss of synapses in embryonic hippocampal neurons. Attenuating the DNA damage response after optic nerve injury is also neuroprotective to retinal ganglion cells and promotes dramatic regeneration of their neurites both in vitro and in vivo. Dorsal root ganglion neurons similarly regenerate when the DNA damage response is targeted in vitro and in vivo and this strategy also induces significant restoration of lost function after spinal cord injury. We conclude that muting the DNA damage response in the nervous system is neuroprotective in multiple neurological disorders. Our results point to new therapies to maintain or repair the nervous system.

SUBMITTER: Tuxworth RI

PROVIDER: S-EPMC7425387 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Attenuating the DNA damage response to double-strand breaks restores function in models of CNS neurodegeneration.

Tuxworth Richard I RI Taylor Matthew J MJ Martin Anduaga Ane A Hussien-Ali Alaa A Chatzimatthaiou Sotiroula S Longland Joanne J Thompson Adam M AM Almutiri Sharif S Alifragis Pavlos P Kyriacou Charalambos P CP Kysela Boris B Ahmed Zubair Z

Brain communications 20190702 1

DNA double-strand breaks are a feature of many acute and long-term neurological disorders, including neurodegeneration, following neurotrauma and after stroke. Persistent activation of the DNA damage response in response to double-strand breaks contributes to neural dysfunction and pathology as it can force post-mitotic neurons to re-enter the cell cycle leading to senescence or apoptosis. Mature, non-dividing neurons may tolerate low levels of DNA damage, in which case muting the DNA damage res ...[more]

PMID: 32954257

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Project description: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.

Dataset Information

Attenuating the DNA damage response to double-strand breaks restores function in models of CNS neurodegeneration.

Publications

Attenuating the DNA damage response to double-strand breaks restores function in models of CNS neurodegeneration.

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