Dopamine Cytotoxicity on SH-SY5Y Cells: Involvement of α-Synuclein and Relevance in the Neurodegeneration of Sporadic Parkinson's Disease.

The cytotoxicity of dopamine on cultured cells of neural origin has been used as a tool to explore the mechanisms of dopaminergic neurodegeneration in Parkinson's disease. In the current study, we have shown that dopamine induces a dose-dependent (10-40 µM) and time-dependent (up to 96 h) loss of cell viability associated with mitochondrial dysfunction and increased intra-cellular accumulation of α-synuclein in cultured SH-SY5Y cells. Dopamine-induced mitochondrial dysfunction and the loss of cell viability under our experimental conditions could be prevented by cyclosporine, a blocker of mitochondrial permeability transition pore, as well as the antioxidant N-acetylcysteine. Interestingly, the dopamine effects on cell viability and mitochondrial functions were significantly prevented by knocking down α-synuclein expression by specific siRNA. Our results suggest that dopamine cytotoxicity is mediated by α-synuclein acting on the mitochondria and impairing its bioenergetic functions.

Biochemical deficits and cognitive decline in brain aging: Intervention by dietary supplements.

The aging of brain in the absence of neurodegenerative diseases, usually called non-pathological brain aging or normal cognitive aging, is characterized by an impairment of memory and cognitive functions. The underlying cellular and molecular changes in the aging brain that include oxidative damage, mitochondrial impairment, changes in glucose-energy metabolism and neuroinflammation have been reported widely from animal experiments and human studies. The cognitive deficit of non-pathological brain aging is the resultant of such inter-dependent and reinforcing molecular pathologies which have striking similarities with those operating in Alzheimer's disease which causes progressive, irreversible and a devastating form of dementia and cognitive decline in the elderly people. Further, this article has described elaborately how nutraceuticals present in a wide variety of plants, fruits and seeds, natural vitamins or their analogues, synthetic antioxidants and other compounds taken with the diet can ameliorate the cognitive decline of brain aging by correcting the biochemical alterations at multiple levels. The clinical usefulness of such dietary supplements should be examined both for normal brain aging and Alzheimer's disease through randomized controlled trials.

Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in Alzheimer's disease and Parkinson's disease.

Alzheimer's disease and Parkinson's disease are two common neurodegenerative diseases of the elderly people that have devastating effects in terms of morbidity and mortality. The predominant form of the disease in either case is sporadic with uncertain etiology. The clinical features of Parkinson's disease are primarily motor deficits, while the patients of Alzheimer's disease present with dementia and cognitive impairment. Though neuronal death is a common element in both the disorders, the postmortem histopathology of the brain is very characteristic in each case and different from each other. In terms of molecular pathogenesis, however, both the diseases have a significant commonality, and proteinopathy (abnormal accumulation of misfolded proteins), mitochondrial dysfunction and oxidative stress are the cardinal features in either case. These three damage mechanisms work in concert, reinforcing each other to drive the pathology in the aging brain for both the diseases; very interestingly, the nature of interactions among these three damage mechanisms is very similar in both the diseases, and this review attempts to highlight these aspects. In the case of Alzheimer's disease, the peptide amyloid beta (Aß) is responsible for the proteinopathy, while α-synuclein plays a similar role in Parkinson's disease. The expression levels of these two proteins and their aggregation processes are modulated by reactive oxygen radicals and transition metal ions in a similar manner. In turn, these proteins - as oligomers or in aggregated forms - cause mitochondrial impairment by apparently following similar mechanisms. Understanding the common nature of these interactions may, therefore, help us to identify putative neuroprotective strategies that would be beneficial in both the clinical conditions.