DNA repair deficiency in neurodegeneration

https://doi.org/10.1016/j.pneurobio.2011.04.013Get rights and content

Abstract

Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative base lesions is base excision repair, and such repair is crucial for neurons given their high rates of oxygen metabolism. Mismatch repair corrects base mispairs generated during replication and evidence indicates that oxidative DNA damage can cause this pathway to expand trinucleotide repeats, thereby causing Huntington's disease. Single-strand breaks are common DNA lesions and are associated with the neurodegenerative diseases, ataxia-oculomotor apraxia-1 and spinocerebellar ataxia with axonal neuropathy-1. DNA double-strand breaks are toxic lesions and two main pathways exist for their repair: homologous recombination and non-homologous end-joining. Ataxia telangiectasia and related disorders with defects in these pathways illustrate that such defects can lead to early childhood neurodegeneration. Aging is a risk factor for neurodegeneration and accumulation of oxidative mitochondrial DNA damage may be linked with the age-associated neurodegenerative disorders Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Mutation in the WRN protein leads to the premature aging disease Werner syndrome, a disorder that features neurodegeneration. In this article we review the evidence linking deficiencies in the DNA repair pathways with neurodegeneration.

Highlights

Neurological disease is a major symptom of genomic instability disorders. ► Deficient DNA repair is linked to progressive neurodegeneration. ► Several hereditary ataxia disorders are characterized by defective DNA repair. ► Mitochondrial DNA damage is implicated in the age-associated Alzheimer's disease. ► Neurodegeneration is a feature of the premature aging disorder Werner syndrome.

Introduction

Amongst the fundamental processes, crucial for viability of organisms, including humans, are appropriate cellular signaling responses to DNA damage and the ability to repair such damage. Our cells are constantly exposed to DNA damage caused by endogenous sources such as reactive oxygen species and exogenous sources such as mutagens and radiation. To protect against this damage all cells have various DNA repair pathways. The four major pathways for repairing damage to bases are nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR) and double-strand break repair (DSBR) (Fig. 1). NER excises bulky helix-distorting DNA lesions and BER repairs damage to a single nucleotide base, whereas MMR corrects mismatches of the normal bases; such as failure to maintain normal Watson–Crick base pairing. Breakage of the DNA backbone also occurs, either in the form of a single-strand break (SSB) or a double-strand break (DSB). SSBs are handled by the BER pathway. The repair of DNA DSBs involves one of two mechanisms: non-homologous end-joining (NHEJ) or homologous recombination (HR). NHEJ directly joins the broken ends, whereas HR uses the intact sister chromatid as a template for repair. In addition, a type of repair termed direct reversal (DR) can reverse some forms of base damage without removing the base. Translesion DNA synthesis (TLS) uses specialized DNA polymerases to replicate past lesions in the DNA, which although more error-prone than BER, NER and MMR, may reduce the immediate danger of DSBs (Prakash and Prakash, 2002).

Deficiencies in DNA repair pathways can result in reduced stability of the cellular chromosomes which in turn can lead to mutagenesis, cellular dysfunction and aberrant phenotypes. Such genomic instability would be expected to potentially increase the risk of cancer, and indeed several hereditary DNA repair deficiency diseases (e.g. Xeroderma Pigmentosum are associated with increased cancer risk). Another major clinical feature of such deficiencies is neurological disease, and accordingly, DNA repair deficiencies are implicated in various diseases that feature progressive neurodegeneration. In the central nervous system (CNS), higher levels of DNA damage either due to increased exposure to damaging agents and/or defective repair of DNA, can lead to pronounced neuropathology. The brain consists largely of non-proliferative neuronal cells and is therefore particularly vulnerable to defective DNA repair that would lead to “accumulation” (more accurately, a greater steady-state level) of unrepaired DNA lesions. These DNA lesions have been proposed to be the cause of the neuropathology observed in several neurodegenerative disorders.

Progressive neurodegeneration occurs when the loss of neuronal structure or function leads to a decline in the number of neurons due to apoptotic cell death. The most consistent risk factor for developing a progressive neurodegenerative disease is aging. With age often comes a decline in brain volume and function, which similarly to neurodegenerative disease can be attributable to the permanent loss of neurons (Brazel and Rao, 2004). The “free radical theory of aging” hypothesizes that accumulation of unrepaired oxidative damage leads to the cellular decline and associated age-related deterioration (Harman, 1981). Considerable circumstantial evidence supports the role of oxidative damage in the aging process (Balaban et al., 2005, Bokov et al., 2004, Golden et al., 2002, Sinclair, 2005), and neurons have very high rates of oxygen metabolism. In view of this it has been suggested that deficiencies in the repair of oxidative DNA damage with aging, correlates with the cognitive decline and neurodegenerative diseases that are more prominent in the aged population (Weissman et al., 2007a). Mitochondria, the main cellular energy generators, are vital for proper neuronal function and survival, and their dysfunction have been linked to neurodegeneration. In addition, it has been suggested by the “mitochondrial theory of aging” that accumulation of mitochondrial damage is the cause of the normal aging process (Harman, 1972).

In this review, we present an overview of the current understanding of the molecular basis for neuronal DNA repair deficiencies associated with neurodegeneration. This will be done by exploring the evidence gained from the study of both inherited and age-associated neurodegenerative diseases. Included are brief descriptions with illustrations of various pathways of DNA repair that we hope will be helpful to readers not already intimately familiar with these important cellular pathways.

Section snippets

Nucleotide excision repair (NER)

Damage from ultraviolet (UV) radiation and reactive oxygen species can generate helix-distorting DNA lesions. The DNA repair process responsible for removing such lesions is the nucleotide excision repair (NER) pathway. NER is a highly conserved and versatile multistep pathway capable of repairing lesions such as UV-induced cyclobutane pyrimidine dimers and 6–4 photoproducts, intra-strand cross-links (Niedernhofer et al., 2004), DNA-protein cross-links (Nouspikel, 2008) and some DNA adducts

Base excision repair (BER)

DNA is inherently unstable due to spontaneous hydrolytic decay and due to modification by both endogenous and exogenous alkylating agents (Lindahl, 1993). In addition reactive oxygen species (ROS), such as the highly reactive hydroxyl radical (OH), superoxide anion (O2•−) and hydrogen peroxide (H2O2) are generated as a result of normal cellular metabolism. ROS is genotoxic and capable of damaging DNA by generating various oxidative DNA lesions with base or sugar damage (Evans et al., 2004,

Mismatch repair (MMR)

DNA mismatch repair (MMR) is a highly conserved pathway that removes base–base mismatches and insertion-deletion loops that arise during DNA replication and recombination, thereby improving the fidelity of replication 50–1000-fold (Hsieh and Yamane, 2008, Jiricny, 2006). Base–base mismatches are created when errors escape from the proofreading function of DNA polymerases. Insertion-deletion loops arise when primer and template strand in a microsatellite dissociate and re-anneal incorrectly,

Single-strand break repair (SSBR)

SSBs are some of the most common lesions found in chromosomal DNA and they can arise in two different ways: (i) indirectly, via enzymatic cleavage of the phosphodiester backbone. Cleavage occurs during BER of oxidative base damage generated by the attack of ROS (Connelly and Leach, 2004), and also during DNA topoisomerase I (TOP1) activity (Pommier et al., 2003). (ii) Directly, induced by the oxidative damage generated by the attack of ROS such as OH, O2•− and H2O2, or by ionizing radiation.

Double-strand break repair (DSBR)

One of the most toxic and mutagenic lesions is the DNA double-strand break (DSB), as chromosomal breakage may result in an extreme loss of genetic integrity. DSBs can be induced by exogenous sources, such as ionizing radiation and exposure to genotoxic compounds that directly or indirectly damage DNA. DSBs can also be induced by endogenous sources, such as the ROS generated by cellular metabolism, replication fork collapse during DNA replication and repair events, and during meiotic

Mitochondria and neurons

Mitochondria are membrane-enclosed organelles that generate most of the ATP supply in eukaryotic cells, including neurons. To generate ATP high-energy electrons must be transported through the electron transport chain at the inner mitochondrial membrane. This process leads to the generation of ROS when high-energy electrons react with O2 to form O2, which in turn leads to generation of H2O2 and OH. While the mitochondria have various antioxidant enzymes to deactivate these highly reactive

Human RecQ helicases

Helicases are ATP-hydrolysis powered motor proteins that separate the two complementary strands of nucleic acid duplexes. Humans posses five distinct DNA helicases of the RecQ family: WRN, BLM, RECQ1, RECQ4 and RECQ5 (van Brabant et al., 2000). Human RecQ helicases are active in replication, recombination, DNA repair and possibly transcription, chromatin structure regulation and telomere maintenance (Bohr, 2008). These functions provide the RecQ helicases with a key role in maintaining genomic

Conclusion

The neurodegenerative diseases examined in this review highlight the importance of DNA repair in maintaining genomic integrity in the CNS, and implicates DNA damage and DNA repair deficiency in the aging of the brain. Much work still needs to be done to better understand the role of DNA repair enzymes and pathways in neurons. In particular, it would be of great interest to determine and clarify if certain neuronal subpopulations are more vulnerable to the effects of DNA repair deficiencies

Acknowledgements

We thank members of the Laboratory for DNA repair and Aging, Dept Molecular Biology, Aarhus University, Denmark and members of the Laboratory of Molecular Gerontology, NIA-NIH (Baltimore, MD) – especially Deborah Croteau for critically reading the manuscript.

D.K. Jeppesen was supported by the Danish Cancer Society and part of this work was supported by a grant from The Velux Foundation to the Danish Aging Research Center.

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