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Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis journal homepage: www.elsevier.com/locate/molmut Community address: www.elsevier.com/locate/mutres
Review
DNA damage in neurodegenerative diseases Fabio Coppedè ∗ , Lucia Migliore ∗∗ Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
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Article history: Available online xxx Keywords: Alzheimer’s disease Parkinson’s disease Amyotrophic Lateral Sclerosis DNA damage Chromosome damage Epigenetics
a b s t r a c t Following the observation of increased oxidative DNA damage in nuclear and mitochondrial DNA extracted from post-mortem brain regions of patients affected by neurodegenerative diseases, the last years of the previous century and the first decade of the present one have been largely dedicated to the search of markers of DNA damage in neuronal samples and peripheral tissues of patients in early, intermediate or late stages of neurodegeneration. Those studies allowed to demonstrate that oxidative DNA damage is one of the earliest detectable events in neurodegeneration, but also revealed cytogenetic damage in neurodegenerative conditions, such as for example a tendency towards chromosome 21 malsegregation in Alzheimer’s disease. As it happens for many neurodegenerative risk factors the question of whether DNA damage is cause or consequence of the neurodegenerative process is still open, and probably both is true. The research interest in markers of oxidative stress was shifted, in recent years, towards the search of epigenetic biomarkers of neurodegenerative disorders, following the accumulating evidence of a substantial contribution of epigenetic mechanisms to learning, memory processes, behavioural disorders and neurodegeneration. Increasing evidence is however linking DNA damage and repair with epigenetic phenomena, thereby opening the way to a very attractive and timely research topic in neurodegenerative diseases. We will address those issues in the context of Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis, which represent three of the most common neurodegenerative pathologies in humans. © 2014 Elsevier B.V. All rights reserved.
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DNA damage in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Oxidative damage to nucleic acids in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Mitochondrial DNA mutations in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Indirectly ROS induced DNA damage in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Cytogenetic damage in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Epigenetics and DNA damage in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DNA damage in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Oxidative damage to nucleic acids in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Mitochondrial DNA mutations in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Indirectly ROS induced DNA damage in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Cytogenetic damage in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Epigenetics and DNA damage in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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∗ Corresponding author at: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Medical School, Via Roma 55, 56126 Pisa, Italy. Tel.: +39 050 2218544. ∗∗ Corresponding author at: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Medical School, Via Roma 55, 56126 Pisa, Italy. Tel.: +39 050 2218549. E-mail addresses: [email protected] (F. Coppedè), [email protected] (L. Migliore). http://dx.doi.org/10.1016/j.mrfmmm.2014.11.010 0027-5107/© 2014 Elsevier B.V. All rights reserved.
Please cite this article in press as: F. Coppedè, L. Migliore, DNA damage in neurodegenerative diseases, Mutat. Res.: Fundam. Mol. Mech. Mutagen. (2014), http://dx.doi.org/10.1016/j.mrfmmm.2014.11.010
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DNA damage in Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Oxidative DNA damage to nucleic acids in Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Mitochondrial DNA mutations in Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Other kinds of DNA damage in Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Epigenetics and DNA damage in Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
2. DNA damage in Alzheimer’s disease
The term neurodegenerative diseases describes a range of hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction resulting from the degeneration of selected neurons in the human brain or spinal cord. As neurons deteriorate, an individual may first experience relatively mild symptoms such as problems with coordination or remembering names. However, with the increasing number of neurons that die, the symptoms get progressively worse, and many of these diseases are fatal. Some of the more well known neurodegenerative disorders include Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS) also referred to as motor neuron disease (MND) or Lou Gehrig’s disease [1]. DNA damage, mainly in the form of oxidative DNA damage and cytogenetic damage, has been largely documented in clinical and preclinical stages of AD brains and peripheral tissues, and is believed to contribute to the neurodegenerative process [2]. Mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage is well documented in PD, and several of the genes causing familial forms of the disease code either for mitochondrial proteins or proteins that are associated with mitochondria, all involved in pathways that elicit oxidative stress or free radical damage [3]. In addition, oxidative DNA damage has been hypothesized to contribute to motor-neuron degeneration in ALS [4]. As it happens for many neurodegenerative risk factors the question of whether DNA damage is cause or consequence of the neurodegenerative process is still open, and probably both is true. Indeed, DNA damage can accumulate in developing brain or spinal cord neurons during early life as a consequence of genetic predisposition, environmental exposure or epigenetic phenomena, leading to the origin of neuronal sub-populations characterized by mutation, copy number variation, or altered expression of certain genes, acting as foci of the neurodegenerative process later in life [5]. DNA damage can also accumulate in post-mitotic differentiated neurons as a consequence of ageing and/or environmental exposures to neurotoxicants, coupled with the age-related reduction of cellular antioxidant defences and DNA repair capabilities, and contribute to the selective degeneration of damaged neurons [6]. However, an increased DNA damage can also partially result from the oxidative damage and the reduced capability to repair it caused by the neurodegenerative process itself, or as a consequence of the cell-cycle re-entry and enhanced neurogenesis put in place to counteract neuronal damage and loss [7]. The accumulating evidence of global epigenetic changes in neurodegenerative diseases suggests that also those mechanisms could contribute to impaired DNA repair and chromosome damage in those disorders [8]. We will address those issues in the context of AD, PD and ALS, that represent three of the most common and studied multi-factorial neurodegenerative diseases.
2.1. Alzheimer’s disease
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Alzheimer’s disease is the most common neurodegenerative disorder and the primary form of dementia among older people. Dementia is a general term to describe a severe decline in mental ability which includes the loss of cognitive functioning such as thinking, remembering and reasoning, coupled with changes in behaviour and personality severe enough to interfere with daily life. It is estimated that almost 36 million people in the world have dementia, and that this number will increase up to 115 millions by 2050, only as a consequence of the global ageing of the population in both developed and developing countries [9]. Concerning AD, dementia ranges in severity with time following the progression of the neurodegenerative process that takes place in selected brain regions, including the temporal and the parietal lobe, and parts of the frontal cortex and cingulate gyrus. After a pre-dementia stage, often defined as amnestic mild cognitive impairment (MCI), dementia usually starts as a mild condition, with patients that easily repeat questions, have problems handling moneys, tend to get lost, and start to have some mood and personality changes. This is followed by a moderate form of the disease often characterized by problems in recognizing family and friends, ending up to the most severe stage, when patients depend completely on others for the performance of daily activities. Therefore, AD is known for placing a great burden on caregivers, which are usually the partner or close relatives, and unfortunately there is no cure to halt the progression of the disease, making it a serious health concern and one of the most costly diseases to the society [9]. 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Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis journal homepage: www.elsevier.com/locate/molmut Community address: www.elsevier.com/locate/mutres
Review
DNA damage in neurodegenerative diseases Fabio Coppedè ∗ , Lucia Migliore ∗∗ Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
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Article history: Available online xxx Keywords: Alzheimer’s disease Parkinson’s disease Amyotrophic Lateral Sclerosis DNA damage Chromosome damage Epigenetics
a b s t r a c t Following the observation of increased oxidative DNA damage in nuclear and mitochondrial DNA extracted from post-mortem brain regions of patients affected by neurodegenerative diseases, the last years of the previous century and the first decade of the present one have been largely dedicated to the search of markers of DNA damage in neuronal samples and peripheral tissues of patients in early, intermediate or late stages of neurodegeneration. Those studies allowed to demonstrate that oxidative DNA damage is one of the earliest detectable events in neurodegeneration, but also revealed cytogenetic damage in neurodegenerative conditions, such as for example a tendency towards chromosome 21 malsegregation in Alzheimer’s disease. As it happens for many neurodegenerative risk factors the question of whether DNA damage is cause or consequence of the neurodegenerative process is still open, and probably both is true. The research interest in markers of oxidative stress was shifted, in recent years, towards the search of epigenetic biomarkers of neurodegenerative disorders, following the accumulating evidence of a substantial contribution of epigenetic mechanisms to learning, memory processes, behavioural disorders and neurodegeneration. Increasing evidence is however linking DNA damage and repair with epigenetic phenomena, thereby opening the way to a very attractive and timely research topic in neurodegenerative diseases. We will address those issues in the context of Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis, which represent three of the most common neurodegenerative pathologies in humans. © 2014 Elsevier B.V. All rights reserved.
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DNA damage in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Oxidative damage to nucleic acids in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Mitochondrial DNA mutations in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Indirectly ROS induced DNA damage in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Cytogenetic damage in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Epigenetics and DNA damage in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DNA damage in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Oxidative damage to nucleic acids in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Mitochondrial DNA mutations in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Indirectly ROS induced DNA damage in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Cytogenetic damage in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Epigenetics and DNA damage in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
00 00 00 00 00 00 00 00 00 00 00 00 00 00 00
∗ Corresponding author at: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Medical School, Via Roma 55, 56126 Pisa, Italy. Tel.: +39 050 2218544. ∗∗ Corresponding author at: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Medical School, Via Roma 55, 56126 Pisa, Italy. Tel.: +39 050 2218549. E-mail addresses: [email protected] (F. Coppedè), [email protected] (L. Migliore). http://dx.doi.org/10.1016/j.mrfmmm.2014.11.010 0027-5107/© 2014 Elsevier B.V. All rights reserved.
Please cite this article in press as: F. Coppedè, L. Migliore, DNA damage in neurodegenerative diseases, Mutat. Res.: Fundam. Mol. Mech. Mutagen. (2014), http://dx.doi.org/10.1016/j.mrfmmm.2014.11.010
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2
4.
DNA damage in Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Oxidative DNA damage to nucleic acids in Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Mitochondrial DNA mutations in Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Other kinds of DNA damage in Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Epigenetics and DNA damage in Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
2. DNA damage in Alzheimer’s disease
The term neurodegenerative diseases describes a range of hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction resulting from the degeneration of selected neurons in the human brain or spinal cord. As neurons deteriorate, an individual may first experience relatively mild symptoms such as problems with coordination or remembering names. However, with the increasing number of neurons that die, the symptoms get progressively worse, and many of these diseases are fatal. Some of the more well known neurodegenerative disorders include Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS) also referred to as motor neuron disease (MND) or Lou Gehrig’s disease [1]. DNA damage, mainly in the form of oxidative DNA damage and cytogenetic damage, has been largely documented in clinical and preclinical stages of AD brains and peripheral tissues, and is believed to contribute to the neurodegenerative process [2]. Mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage is well documented in PD, and several of the genes causing familial forms of the disease code either for mitochondrial proteins or proteins that are associated with mitochondria, all involved in pathways that elicit oxidative stress or free radical damage [3]. In addition, oxidative DNA damage has been hypothesized to contribute to motor-neuron degeneration in ALS [4]. As it happens for many neurodegenerative risk factors the question of whether DNA damage is cause or consequence of the neurodegenerative process is still open, and probably both is true. Indeed, DNA damage can accumulate in developing brain or spinal cord neurons during early life as a consequence of genetic predisposition, environmental exposure or epigenetic phenomena, leading to the origin of neuronal sub-populations characterized by mutation, copy number variation, or altered expression of certain genes, acting as foci of the neurodegenerative process later in life [5]. DNA damage can also accumulate in post-mitotic differentiated neurons as a consequence of ageing and/or environmental exposures to neurotoxicants, coupled with the age-related reduction of cellular antioxidant defences and DNA repair capabilities, and contribute to the selective degeneration of damaged neurons [6]. However, an increased DNA damage can also partially result from the oxidative damage and the reduced capability to repair it caused by the neurodegenerative process itself, or as a consequence of the cell-cycle re-entry and enhanced neurogenesis put in place to counteract neuronal damage and loss [7]. The accumulating evidence of global epigenetic changes in neurodegenerative diseases suggests that also those mechanisms could contribute to impaired DNA repair and chromosome damage in those disorders [8]. We will address those issues in the context of AD, PD and ALS, that represent three of the most common and studied multi-factorial neurodegenerative diseases.
2.1. Alzheimer’s disease
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Alzheimer’s disease is the most common neurodegenerative disorder and the primary form of dementia among older people. Dementia is a general term to describe a severe decline in mental ability which includes the loss of cognitive functioning such as thinking, remembering and reasoning, coupled with changes in behaviour and personality severe enough to interfere with daily life. It is estimated that almost 36 million people in the world have dementia, and that this number will increase up to 115 millions by 2050, only as a consequence of the global ageing of the population in both developed and developing countries [9]. Concerning AD, dementia ranges in severity with time following the progression of the neurodegenerative process that takes place in selected brain regions, including the temporal and the parietal lobe, and parts of the frontal cortex and cingulate gyrus. After a pre-dementia stage, often defined as amnestic mild cognitive impairment (MCI), dementia usually starts as a mild condition, with patients that easily repeat questions, have problems handling moneys, tend to get lost, and start to have some mood and personality changes. This is followed by a moderate form of the disease often characterized by problems in recognizing family and friends, ending up to the most severe stage, when patients depend completely on others for the performance of daily activities. Therefore, AD is known for placing a great burden on caregivers, which are usually the partner or close relatives, and unfortunately there is no cure to halt the progression of the disease, making it a serious health concern and one of the most costly diseases to the society [9]. 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