Intravesicular Localization and Exocytosis of α-Synuclein and its Aggregates

TLDR

α‑Synuclein, especially its aggregated forms, is linked to Parkinson’s disease, yet its normal biology and intracellular versus extracellular roles remain poorly understood. We demonstrate that a minority of newly synthesized α‑synuclein is secreted via unconventional, ER/Golgi‑independent exocytosis, that intravesicular α‑synuclein aggregates more readily, and that both monomeric and aggregated forms are released at higher levels during proteasomal or mitochondrial stress, suggesting that intravesicular localization and secretion are normal features that may contribute to disease.

Abstract

α-Synuclein (α-syn), particularly in its aggregated forms, is implicated in the pathogenesis of Parkinson's disease and other related neurological disorders. However, the normal biology of α-syn and how it relates to the aggregation of the protein are not clearly understood. Because of the lack of the signal sequence and its predominant localization in the cytosol, α-syn is generally considered exclusively an intracellular protein. Contrary to this assumption, here, we show that a small percentage of newly synthesized α-syn is rapidly secreted from cells via unconventional, endoplasmic reticulum/Golgi-independent exocytosis. Consistent with this finding, we also demonstrate that a portion of cellular α-syn is present in the lumen of vesicles. Importantly, the intravesicular α-syn is more prone to aggregation than the cytosolic protein, and aggregated forms of α-syn are also secreted from cells. Furthermore, secretion of both monomeric and aggregated α-syn is elevated in response to proteasomal and mitochondrial dysfunction, cellular defects that are associated with Parkinson's pathogenesis. Thus, intravesicular localization and secretion are part of normal life cycle of α-syn and might also contribute to pathological function of this protein.