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Parkinson’s disease (PD) is the most frequent agerelated movement disorder due to the loss of dopaminergic neurons. It is characterized at the histological level by the presence of intracellular lesions named Lewy bodies and cell death stigmata. The main constituent of Lewy bodies is α-synuclein (α-syn), a phosphoprotein that is strongly linked to the etiology of both genetic and sporadic PD. α-syn is a protein contributing to dopaminergic neuronal health and numerous evidences indicate that, in physiological conditions α-syn is neuroprotective while, in PD-related pathological conditions, it becomes aggregated and thereby, neurotoxic[1 , 2]. More than ten years ago, we were first to show that wild-type α-syn displayed antiapoptotic properties (OMIM entry 163890) and that this function was abolished by its aggregation [3, 4]. We showed that α-syn overexpression in telencephalon mouse neurons led to decreased cell death via the down-regulation of the tumor suppressor p53 (a key transcription factor involved in apoptosis regulation in neurodegenerative disorders [5, 6]) at both protein and transcriptional levels and that this phenotype was abolished by the pro-oxidant neurotoxin and PDinducer, 6-hydroxydopamine (6OHDA) [4]. Importantly, we have demonstrated that 6OHDA triggers α-syn loss of function by modifying its biochemical properties and catabolic fate [7]. This was explained by our two-points demonstration that: 1) 6OHDA pro-oxidant properties promote in vitro α-syn aggregation; 2) 6OHDA-mediated oxidation abolishes in vitro and cellular proteasomal activities and thus, proteasome-mediated α-syn degradation. Therefore, the accumulation of α-syn by 6OHDA-mediated proteasomal inhibition leads to α-syn aggregation and dysfunction. These seminal observations gave an anatomical support to the paradoxical observation that α-syn aggregation occurs selectively in dopaminergic brain regions (i.e regions where 6OHDA can be produced) while α-syn is widely spread over whole brain. This led us to propose that PD, at least in sporadic cases, is much more related to a cell-specific susceptibility to dopaminergic toxins rather than linked to the presence of a subset of pathological protein triggers. We have recently demonstrated that the functional interplay by which α-syn controls p53 is not unidirectional and is controlled by a feedback loop. Thus, endogenous

α-synuclein and p53 functional interplay in physiopathological contexts