Progressive degeneration of dopaminergic neurons of the substantia nigra and the resulting dopamine deficiency in the striatum are neuropathological basis of the movement disorders in Parkinson's disease (PD). Neuromelanin-containing neurons are particularly susceptible to degeneration and their depigmentation is the hallmark of the advanced disease. The proposed mechanisms underlaying the pathogenesis and progression of neurodegeneration in the substantia nigra include iron-catalyzed oxidative stress, mitochondrial dysfunctions, inflammation and disturbances of protein metabolism. This review presents some new concepts concerning important but ambiguous role of neuromelanin in the above mentioned processes. It seems that the imbalance between cytoprotective and cytotoxic action of the pigment may cause neuronal death via mitochondrial oxidative stress, inhibition of ubiquitine-proteasome system and alpha-synuclein accumulation. Extraneuronal melanin may contribute to chronic inflammation by excessive secretion of cytokines and nitric oxide due to prolonged microglia activation. Recent reports suggest a possible role of the lipid component of neuromelanin in pigment-dependent cytotoxicity.
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