Intercellular transmission of alpha-synuclein

An emerging theme in Parkinson's disease (PD) is the propagation of alpha-synuclein pathology as the disease progresses. Research involving the injection of preformed alpha-synuclein fibrils (PFFs) in animal models has recapitulated the pathological spread observed in PD patients. At the cellular and molecular levels, this intercellular spread requires the translocation of alpha-synuclein across various membrane barriers. Recent studies have identified subcellular organelles and protein machineries that facilitate these processes. In this review, we discuss the proposed pathways for alpha-synuclein intercellular transmission, including unconventional secretion, receptor-mediated uptake, endosome escape and nanotube-mediated transfer. In addition, we advocate for a rigorous examination of the evidence for the localization of alpha-synuclein in extracellular vesicles.