Conclusions

A few years ago we speculated on our opinion that, as cancer is a well-known multistep process, also neurodegeneration could be due to multiple pathogenic mechanisms in which an initiator event, such as the inheritance of a particular gene or the contribution of gene-environment interactions, can lead to the formation of an anomalous protein in some areas of the brain, and that the subsequent accumulation of this product continues until a critical concentration is reached for cell survival and is able to trigger several responses ending with cellular death (162). There is now strong evidence from genetic, transgenic mouse, and biochemical studies to support the idea that the accumulation of protein aggregates in the brain plays a fundamental role in the pathogenesis of several neurodegenerative diseases, including AD, PD, dementia with Lewy bodies, HD, and prion diseases (163), and the current opinion is that neurodegenerative diseases are not the result of a single-hit event, but rather a several-step process involving genetic, epige-netic, and environmental events; they probably act together, perhaps in conjunction with stochastic effects, to influence disease risk and presentation (120). Increasing evidence indicates that the accumulation of aberrant proteins, their aggregation, dysfunction of the ubiquitin-proteasome system, oxidative damage, mitochondrial injury, and the disruption of the neuronal transport and functions represent a unifying pathway in several neurodegenerative diseases (120). Several causative and susceptibility genes and their interplay with environmental factors in the etiology of neurodegeneration still requires to be discovered or clarified; however recent evidence discussed in this chapter and indicating in the neuronal cell cycle re-entry a possible candidate mechanism to allow DNA oxidative damage repair, open a interesting field of investigation for other possible candidate genes, and lead to the opinion of a possible interplay between the formation of damaged intracellular components, including proteins, lipids, RNA and DNA, and their repair in the slow progression of neuronal degenerative death. Recent advances in the fields of genomics and proteomics together with studies on centenarians are promising for a better understanding of the complex mechanisms leading to neurodegeneration and/or neuroprotection, and the emerging role for oxidative stress as an early event in the neurodegenerative process is promising for the development of primary prevention strategies.

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