AbstractAlpha‐synuclein (ASYN) is a major constituent of the typical protein aggregates observed in several neurodegenerative diseases that are collectively referred to as synucleinopathies. A causal involvement ofASYNin the initiation and progression of neurological diseases is suggested by observations indicating that single‐point (e.g., A30P, A53T) or multiplication mutations of the gene encoding forASYNcause early onset forms of Parkinson's disease (PD). The relative regional specificity ofASYNpathology is still a riddle that cannot be simply explained by its expression pattern. Also, transgenic over‐expression ofASYNin mice does not recapitulate the typical dopaminergic neuronal death observed inPD. Thus, additional factors must contribute toASYN‐related toxicity. For instance, synucleinopathies are usually associated with inflammation and elevated levels of oxidative stress in affected brain areas. In turn, these conditions favor oxidative modifications ofASYN. Among these modifications, nitration of tyrosine residues, formation of covalentASYNdimers, as well as methionine sulfoxidations are prominent examples that are observed in post‐mortemPDbrain sections. Oxidative modifications can affectASYNaggregation, as well as its binding to biological membranes. This would affect neurotransmitter recycling, mitochondrial function and dynamics (fission/fusion),ASYN's degradation within a cell and, possibly, the transfer of modifiedASYNto adjacent cells. Here, we propose a model on how covalent modifications ofASYNlink energy stress, altered proteostasis, and oxidative stress, three major pathogenic processes involved inPDprogression. Moreover, we hypothesize thatASYNmay act physiologically as a catalytically regenerated scavenger of oxidants in healthy cells, thus performing an important protective role prior to the onset of disease or during aging.