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

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


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.


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



Alzheimer’s disease


Amyotrophic lateral sclerosis


Antisense oligonucleotides


Alternative NHEJ


Ataxia telangiectasia mutated


Ataxia telangiectasia and Rad3 related


Base excision repair


Breast and ovarian cancer susceptibility protein 1


Chromosome 9 open reading frame 72


CtBP-interacting protein


CDKN1A-interacting zinc finger protein 1


DNA damage response


Deoxyribonucleic acid


DNA double-strand-breaks


DNA-dependent protein kinase catalytic subunit


DNA-dependent protein kinase


Exonuclease 1


Fused in sarcoma


Histone deacetylase 1


H2A histone family member X


Homologous recombination


DNA ligase IV


Mismatch repair


Microhomology-mediated end joining


Meiotic recombination11


Nijmegen breakage syndrome 1


Nucleotide excision repair


Non-homologous end joining


Parkinson’s disease


Phosphatidylinositol-3 kinase-related kinases


Poly (ADP-ribose) polymerase 1


Structural maintenance of chromosomes 1A


Superoxide dismutase 1


Transactivation response DNA-binding protein

Topo Iiβ

Topoisomerase Iiβ


X-ray cross-complementing protein 4


XRCC4-like factor


Stress granule


p53-binding protein 1


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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