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

  • Nidheesh Thadathil
  • Roderick Hori
  • Jianfeng Xiao
  • Mohammad Moshahid KhanEmail author
Review

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.

Keywords

DNA damage Genomic instability, Neurodegeneration Alzheimer’s disease Parkinson’s disease DNA repair 

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

Notes

Funding information

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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

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© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Neurology, College of MedicineUniversity of Tennessee Health Science CenterMemphisUSA
  2. 2.Department of Microbiology, Immunology and BiochemistryUniversity of Tennessee Health Science CenterMemphisUSA
  3. 3.Division of Rehabilitation Sciences and Department of Physical Therapy, College of Health ProfessionsUniversity of Tennessee Health Science CenterMemphisUSA
  4. 4.Department of NeurologyUniversity of Tennessee Health Science CenterMemphisUSA

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