Kostas Vekrellis1, Evangelia Emmanouilidou2, Maria Xilouri3 and Leonidas Stefanis3,4 1Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece 2Laboratory of Biochemistry, Department of Chemistry, National and Kapodistrian University of Athens, Athens 15784, Greece 3Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece 4First Department of Neurology, National and Kapodistrian University of Athens Medical School, Athens 11528, Greece; and Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece Correspondence: lstefanisbioacaddemy.gr

α-Synuclein (AS) is a small presynaptic protein that is genetically, biochemically, and neuropathologically linked to Parkinson's disease (PD) and related synucleinopathies. We present here a review of the topic of this relationship, focusing on more recent knowledge. In particular, we review the genetic evidence linking AS to familial and sporadic PD, including a number of recently identified point mutations in the SNCA gene. We briefly go over the relevant neuropathological findings, stressing the evidence indicating a correlation between aberrant AS deposition and nervous system dysfunction. We analyze the structural characteristics of the protein, in relation to both its physiologic and pathological conformations, with particular emphasis on posttranslational modifications, aggregation properties, and secreted forms. We review the interrelationship of AS with various cellular compartments and functions, with particular focus on the synapse and protein degradation systems. We finally go over the recent exciting data indicating that AS can provide the basis for novel robust biomarkers in the field of synucleinopathies, while at the same time results from the first clinical trials specifically targeting AS are being reported.