The αSynuclein half-life conundrum

alpha Synuclein (alpha Syn) misfolding and aggregation frequently precedes neuronal loss associated with Parkinson's Disease (PD) and other Synucleinopathies. The progressive buildup of pathological alpha Syn species results from alterations on alpha Syn gene and protein sequence, increased local concentrations, variations in alpha Syn interactome and protein network. Therefore, under physiological conditions, it is mandatory to regulate alpha Syn proteostasis as an equilibrium among synthesis, trafficking, degradation and extracellular release. In this frame, a crucial parameter is protein half-life. It provides indications of the turnover of a specific protein and depends on mRNA synthesis and translation regulation, subcellular localization, function and clearance by the designated degradative pathways. For alpha Syn, the molecular mechanisms regulating its proteostasis in neurons have been extensively investigated in various cellular models, either using biochemical or imaging approaches. Nevertheless, a converging estimate of alpha Syn half-life has not emerged yet. Here, we discuss the challenges in studying alpha Syn proteostasis under physiological and pathological conditions, the advantages and disadvantages of the experimental strategies proposed so far, and the relevance of determining alpha Syn half-life from a translational perspective.