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DNA double-strand breaks: a potential therapeutic target for neurodegenerative diseases

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Abstract

The complexity of neurodegeneration restricts the ability to understand and treat the neurological disorders affecting millions of people worldwide. Therefore, there is an unmet need to develop new and more effective therapeutic strategies to combat these devastating conditions and that will only be achieved with a better understanding of the biological mechanism associated with disease conditions. Recent studies highlight the role of DNA damage, particularly, DNA double-strand breaks (DSBs), in the progression of neuronal loss in a broad spectrum of human neurodegenerative diseases. This is not unexpected because neurons are prone to DNA damage due to their non-proliferative nature and high metabolic activity. However, it is not clear if DSBs is a primary driver of neuronal loss in disease conditions or simply occurs concomitant with disease progression. Here, we provide evidence that supports a critical role of DSBs in the pathogenesis of the neurodegenerative diseases. Among different kinds of DNA damages, DSBs are the most harmful and perilous type of DNA damage and can lead to cell death if left unrepaired or repaired with error. In this review, we explore the current state of knowledge regarding the role of DSBs repair mechanisms in preserving neuronal function and survival and describe how DSBs could drive the molecular mechanisms resulting in neuronal death in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. We also discuss the potential implications of DSBs as a novel therapeutic target and prognostic marker in patients with neurodegenerative conditions.

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Abbreviations

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

ASOs:

Antisense oligonucleotides

A-NHEJ:

Alternative NHEJ

ATM:

Ataxia telangiectasia mutated

ATR:

Ataxia telangiectasia and Rad3 related

BER:

Base excision repair

BRCA1:

Breast and ovarian cancer susceptibility protein 1

C9ORF72:

Chromosome 9 open reading frame 72

CtIP:

CtBP-interacting protein

CIZ1:

CDKN1A-interacting zinc finger protein 1

DDR:

DNA damage response

DNA:

Deoxyribonucleic acid

DSBs:

DNA double-strand-breaks

DNA-PKcs:

DNA-dependent protein kinase catalytic subunit

DNA-PK:

DNA-dependent protein kinase

Exo1:

Exonuclease 1

FUS:

Fused in sarcoma

HDAC1:

Histone deacetylase 1

H2AX:

H2A histone family member X

HR:

Homologous recombination

LIG4:

DNA ligase IV

MMR:

Mismatch repair

MMEJ:

Microhomology-mediated end joining

MRE11:

Meiotic recombination11

NBS1:

Nijmegen breakage syndrome 1

NER:

Nucleotide excision repair

NHEJ:

Non-homologous end joining

PD:

Parkinson’s disease

PIKK:

Phosphatidylinositol-3 kinase-related kinases

PARP1:

Poly (ADP-ribose) polymerase 1

SMC1A:

Structural maintenance of chromosomes 1A

SOD 1:

Superoxide dismutase 1

TDP-43:

Transactivation response DNA-binding protein

Topo Iiβ :

Topoisomerase Iiβ

XRCC4:

X-ray cross-complementing protein 4

XLF:

XRCC4-like factor

SG:

Stress granule

53BP1:

p53-binding protein 1

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Funding

Our research on DNA damage is supported by Department of Defense grant W81XWH-17-1-0062; William and Ella Owens Medical Research Foundation, NIH R21 GM118962, R03 NS101485, Neuroscience Institute, and the Division of Rehabilitation Sciences, College of Health Professions, University of Tennessee Health Science Center.

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Correspondence to Mohammad Moshahid Khan.

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The authors declare that they have no conflicts of interest.

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EditorialResponsibility: Beth Sullivan

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Thadathil, N., Hori, R., Xiao, J. et al. DNA double-strand breaks: a potential therapeutic target for neurodegenerative diseases. Chromosome Res 27, 345–364 (2019). https://doi.org/10.1007/s10577-019-09617-x

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  • DOI: https://doi.org/10.1007/s10577-019-09617-x

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