Alpha-Synuclein, Oxidative Stress and Autophagy Failure: Dangerous Liaisons in Dopaminergic Neurodegeneration

The molecular mechanisms of neurodegeneration in Parkinson’s disease and the cause of the selective dopaminergic neuronal loss are mostly unknown. Many pathogenetic factors have been found to play a role but the relationships among these factors, together with the reasons of the high vulnerability of dopaminergic neurons to them, have not been completely defined. Only a small fraction of Parkinson’s disease cases have a defined etiology: this fraction include the monogenic hereditary variants of the disease and the sporadic cases determined by prolonged exposition to toxic agents inhibiting mitochondrial complex I, such as 1,1’-dimethyl-4,4’-5 bipyridinium (paraquat), rotenone and 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP). Parkinson’s disease-related toxins and pathogenetic mutations have been indispensable to create cell and animal models with the aim to clarify the molecular physiopathology of the disease. Little is known about the primitive causes of idiopathic Parkinson’s disease, that probably represents a multi-factorial disease influenced by various genetic and environmental factors, all characterized by high incidence in general population. The different risk factors together would contribute to initiate the complex pathogenetic sequence of events leading to the death of dopaminergic neurons. Recently, Parkinson’s disease has been placed in the large category of neurodegenerative diseases caused by protein misfolding. In particular, alpha-synuclein has been proposed as the central and most specific factor implied in the pathogenesis of this syndrome, which, as a consequence, has been classified among synucleinopathies, together with dementia with Lewy bodies and multiple system atrophy, other neurodegenerative diseases having alphasynuclein pathology as a major feature. Aim of this chapter is to provide an organic revision of evidences for the involvement of alpha-synuclein in the pathogenesis of Parkinson’s disease. We will define the mechanisms responsible for the toxic gain of function of ┙-synuclein and the processes triggered by aberrant alpha-synuclein and mediating its neurotoxic effect. Particular attention will be paid to establish the links that correlate the deleterious action of alpha-synuclein with oxidative stress and with the efficiency of the processes involved in the clearance of aberrant