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Review
. 2019 Oct;16(4):948-956.
doi: 10.1007/s13311-019-00768-7.

DNA Damage Repair in Huntington's Disease and Other Neurodegenerative Diseases

T Maiuri  1 , C E Suart  1 , C L K Hung  1 , K J Graham  1 , C A Barba Bazan  1 , R Truant  2
Affiliations
Review

DNA Damage Repair in Huntington's Disease and Other Neurodegenerative Diseases

T Maiuri et al. Neurotherapeutics. 2019 Oct.

Abstract

Recent genome-wide association studies of Huntington's disease (HD) primarily highlighted genes involved in DNA damage repair mechanisms as modifiers of age at onset and disease severity, consistent with evidence that more DNA repair genes are being implicated in late age-onset neurodegenerative diseases. This provides an exciting opportunity to advance therapeutic development in HD, as these pathways have already been under intense investigation in cancer research. Also emerging are the roles of other polyglutamine disease proteins in DNA damage repair mechanisms. A potential universal trigger of oxidative DNA damage shared in these late age-onset diseases is the increase of reactive oxygen species (ROS) in human aging, defining an age-related mechanism that has defied other hypotheses of neurodegeneration. We discuss the potential commonality of DNA damage repair pathways in HD and other neurodegenerative diseases. Potential targets for therapy that may prove beneficial across many of these diseases are also identified, defining nodes in the ataxia telangiectasia-mutated (ATM) complex, mismatch repair, and poly ADP-ribose polymerases (PARPs).

Keywords: Ataxia telangiectasia-mutated (ATM); DNA repair; Huntington’s disease; Oxidative stress; Poly ADP-ribose polymerase (PARP); Spinocerebellar ataxia.

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Figures

Fig. 1
Fig. 1
Proposed mechanism of N6FFA action. Left panel: Products of oxidative DNA damage are excised by the repair machinery yielding N6FFA, which is salvaged to KTP by APRT. KTP is used by CK2 to phosphorylate its targets, including normal huntingtin. The signal dampens naturally as adducts are repaired. Middle panel: Expanded huntingtin is inefficiently phosphorylated and impaired in its scaffolding function, resulting in the accumulation of adducts. Without N6FFA excision and conversion to KTP, the signal is stifled. Right panel: Exogenous N6FFA is salvaged by APRT, providing a source of KTP to activate CK2 signaling and restore repair
Fig. 2
Fig. 2
DNA repair and neuronal energy homeostasis. The combined energetic costs of high metabolic rate, and repair of metabolism by-product–mediated damage, make neurons vulnerable to minor deficiencies in DNA repair proteins with age
See this image and copyright information in PMC

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