Epigenetics in neurodegeneration: A new layer of complexity

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Abstract

Several diseases are known to have a multifactorial origin, depending not only on genetic but also on environmental factors. They are called “complex disorders” and include cardiovascular disease, cancer, diabetes, and neuropsychiatric and neurodegenerative diseases. In the latter class, Alzheimer's (AD) and Parkinson's diseases (PD) are by far the most common in the elderly and constitute a tremendous social and economical problem. Both disorders present familial and sporadic forms and although some polymorphisms and risk factors have been associated with AD and PD, the precise way by which the environment contributes to neurodegeneration is still unclear.

Recent studies suggest that environmental factors may contribute for neurodegeneration through induction of epigenetic modifications, such as DNA methylation, and chromatin remodeling, which may induce alterations in gene expression programs. Epigenetics, which refers to any process that alters gene activity without changing the actual DNA sequence, and leads to modifications that can be transmitted to daughter cells, is a relatively novel area of research that is currently attracting a high level of interest. Epigenetic modulation is present since the prenatal stages, and the aging process is now accepted to be associated with a loss of phenotypic plasticity to epigenetic modifications. Since aging is the most important risk factor for idiopathic AD and PD, it is expected that epigenetic alterations on DNA and/or chromatin structure may also accumulate in neurodegeneration, accounting at least in part to the etiology of these disorders.

Research Highlights

►Complex disorders have a multifactorial origin, depending on both genetic and environmental factors. ►The effect of environmental factors may occur through the induction of epigenetic modifications. ►Aging is associated with epigenetic modulation. ►Alzheimer's and Parkinson's disease are complex disorders in which the sporadic forms are strongly associated with aging. ►Epigenetics may be the missing link to explain the late-onset forms of several neurodegenerative disorders.

Introduction

Neurodegenerative disorders, such as Alzheimer's (AD) and Parkinson's diseases (PD), affect an increasing number of people due to the overall increase in life expectancy. The World Health Organization estimates that by 2025 three-quarters of people over 60 years of age will be living in developing countries (http://www.who.int/hpr/ageing/ActiveAgingPolicyFrame.pdf). Unless novel strategies to prevent or treat these age-related brain disorders are developed, the economical and social impact will be enormous.

The majority of AD and PD cases are sporadic and are thought to arise from the combination of environmental factors and susceptibility genes in ways that are not fully understood. Thus, these disorders are considered highly complex in similarity to the case of cancer, diabetes, and cardiovascular and neuropsychiatric disorders. The complexity of these disorders turns the discovery of therapeutics difficult unless we understand how the environment can affect the organisms and the result in the development of the disease.

Epigenetics, which refers to modifications in gene expression that are controlled by heritable but potentially reversible changes in DNA methylation and/or chromatin structure, is acquired throughout life and depends from environmental clues, such as lifestyle, diet and toxin exposure. The research in this field is now emerging and its effects on aging or in complex diseases such as cancer have started to be shown.

Consequently, since AD and PD are age-related complex disorders, epigenetics might be the missing link between environmental risk factors and the sporadic form of neurodegeneration.

Section snippets

Epidemiology of AD

Currently, it is estimated that one in eight (13%) persons above 65 years old is diagnosed with AD. The prevalence increases to approximately 40% after the age of 85. The number of AD patients is estimated to reach 7.7 million in 2030, constituting a greater than 50% increase from the 5.1 million aged 65 and older who are currently affected. By 2050, this number is projected to reach between 11 million and 16 million if the current state of medical therapeutics is maintained (Alzheimer's

Epidemiology of PD

PD, the second most common neurodegenerative disorder after AD, has an average age of onset of 60 years old and according to the Parkinson's Disease Foundation, it affects about 1 million people in the United States and more than 4 million people worldwide. The prevalence of PD in industrialized countries is generally estimated at about 1–2% of people over 60 years of age. This figure increases to 3% to 5% in people above 85 years old (Lau and Breteler, 2006).

Pathological mechanisms in neurodegenerative diseases

Several lines of investigation have now converged to show that the etiologies of AD and PD share common mechanisms (Bossy-Wetzel et al., 2004). One of the commonalities between AD and PD is the extra- and intracellular accumulation of protein aggregates rich in β-pleated sheet conformation, representing the hallmarks of these two slowly progressive neurodegenerative disorders. Such protein aggregates might arise, in part, as a consequence of impaired proteasomal and/or autophagic removal of the

Clinical and pathological hallmarks of AD

The clinical hallmarks of AD are progressive impairment in memory, judgment, decision-making, orientation to physical surroundings, and language. Diagnosis is based on neurologic examination and the exclusion of other causes of dementia. However a definitive diagnosis can be made only at autopsy to detect the histopathological features of the disease, which include senile plaques composed of insoluble Aβ peptide that accumulates extracellullarly, intracellular neurofibrillary tangles composed

Clinical and pathological hallmarks of PD

PD is characterized by resting tremor, slow and decreased movement (bradykinesia), muscular rigidity, and postural instability. Pathologically, PD patients show loss of dopaminergic neurons in the substantia nigra (SN) pars compacta and frequently have Lewy bodies, eosinophilic intracellular inclusions composed of amyloid-like fibers and α-synuclein (Weintraub et al., 2008).

The Braak staging hypothesis for PD posits that pathology evolves in 6 stages. This staging suggests a pre-motor period in

The complexity of neurodegenerative disorders

In AD and PD, as well as in several other neurodegenerative diseases, there is a strong dichotomy between familial (rare) and non-familial (common) forms. These disorders comprise interactions between the different genes with each other as well as with non-genetic factors. Thus, they are considered complex disorders (Fig. 1) (Bertam and Tanzi, 2005).

Familial and sporadic Alzheimer's disease

Early-onset familial AD accounts for only 5–10% of all cases. The genes implicated in this form of the disease are the genes encoding for amyloid precursor protein (APP), located on chromosome 21q21, the gene encoding for presenilin 1 (PSEN1), located on chromosome 14q24.3, and that encoding for presenilin 2 (PSEN2), on chromosome 1q31–q42 (Ertekin-Taner, 2007). Mutations in APP are located near the cleavage sites of the protein resulting in increased production of the amyloid-β peptide. The

Familial and idiopathic Parkinson's disease

In 5–10% of cases, PD has mainly a genetic component, with both recessive and dominant modes of inheritance. Several genes and chromosomal loci have been linked to familial forms of parkinsonism and are designated as PARK1 to PARK16 (Table 1). These loci are associated with autosomal dominant, recessive, and X-linked forms of the disease. The mode of transmission of PARK16 is not fully understood yet (Hardy et al., 2009).

SNCA, the gene encoding α-synuclein, was the first to be associated with

Aging as a risk factor for neurodegeneration

As previously stated, aging is the major known risk factor for AD and PD. There is a high probability that a person who lives to the age of 85 years will suffer from AD. The aging process is characterized by a loss of phenotypic plasticity of the cells to respond to deleterious effects. Consequently, cells are exposed to an increased amount of oxidative stress, perturbed energy homeostasis, accumulation of damaged proteins and lesions in their nucleic acids. These changes during normal aging are

Epigenetics in neurodegeneration

Neurodegenerative diseases are now believed to be multifactorial processes involving genetic, epigenetic and environmental components.

The epigenome comprises the heritable but potentially reversible changes in gene expression that occur in the absence of changes to the DNA sequence itself. These changes are brought about by DNA methylation and modifications of chromatin, such as acetylation, methylation, phosphorylation, or ubiquitylation of histones (Fig. 2) (Dolinoy and Jirtle, 2008).

Concluding remarks

Several complex disorders, such as AD and PD, have a multifactorial origin, including genetic variations and polymorphisms, which account for the early onset of cases, and environmental factors, such as age, lifestyle, diet, and level of education, all affecting the onset and severity of the late-onset forms. Until recently, it was still unclear how the risk factors may affect these pathways and lead to AD or PD pathogenesis.

Epigenetics may constitute the missing link in the interplay between

Acknowledgements

SM is supported by FCT SFRH/BD/33188/2007. TFO is supported by a Marie Curie International Reintegration Grant (Neurofold) and an EMBO Installation Grant.

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