Despite the fact that Alzheimer’s (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases, their pathogenesis still remains largely not well understood. However, advances during the last few decades in the characterizations of rare mendelian mutations and common risk genes as well as the role of epigenetics have greatly enhanced our understanding for the role of heritability and environmental factors in the development of AD and PD. This paper reviews key findings along their molecular mechanisms while tries to provide an overview of the overall contribution of genetics and epigenetics in the two diseases. Moreover, recent findings on neuronal genetic instability are also mentioned and, finally, a model that tries to integrate the effects of genetics, epigenetics, environment and pathological processes is proposed supporting the hypothesis that few ‘seeding’ pathogenic foci are sufficient to produce generalized pathology.
Introduction and Insight from Twin Studies.
Alzheimer’s (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases affecting about 1% and 0.5-1% in 65-69 years old and up to 50% and 4% respectively in older groups.[1-3] The pathogenesis of the two diseases is heterogeneous and not well understood although the long-standing involvement of specific protein misfolding and aggregation is well characterised in each case. AD presents as an insidious and progressive deterioration of global cognitive functions and is histopathologically recognized by the accumulation of extracellular amyloid-β-containing (Aβ) plaques and intraneuronal deposits of hyperphosphorylated τ protein (pτ) in the form of neurofibrillary tangles (NFTs). Both soluble/prefibrillar and fibrillar Aβ together with pτ are highly implicated in axonal transport failure, deranged dendritic signalling, excitotoxicity and ultimately cell death.[4,5] Similarly, in PD, which predominantly but not solely affects the dopaminergic system leading to a wide range of motor and neuropsychiatric symptoms, α-synuclein-containing intraneuronal Lewis bodies (LBs) are considered hallmark of the disease,[6,7] while the role of deranged protein handling, ubiquitin proteasome system (UPS) and mitochondrial dysfunction, and increased oxidative stress are considered to be pivotal.[8,9]
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