Intravesicular Localization and Exocytosis of α-Synuclein and its Aggregates

Abstract

␣-Synuclein (␣-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 ␣-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, ␣-syn is generally considered exclusively an intracellular protein. Contrary to this assumption, here, we show that a small percentage of newly synthesized ␣-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 ␣-syn is present in the lumen of vesicles. Importantly, the intravesicular ␣-syn is more prone to aggregation than the cytosolic protein, and aggregated forms of ␣-syn are also secreted from cells. Furthermore, secretion of both monomeric and aggregated ␣-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 ␣-syn and might also contribute to pathological function of this protein.

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

“…Numerous strategies directed at reducing the accumulation of these proteins have been developed, including the use of small interfering RNA, antisense RNA [39][40][41][42][43], degrading enzymes (e.g., cathepsin D, neurosin, neprilysin) [44][45][46], chaperonelike molecules that modulate aggregation state (e.g., Hsp70, β-syn) [47][48][49][50], anti-aggregation compounds (e.g., polyphenols) [51][52][53], and immunotherapy (passive, active, and Tcell-based) [54]. Moreover, the recent discovery that toxic oligomeric forms of α-syn and tau accumulate in the plasma membrane and are secreted to the extracellular environment has provided further rationale for the development of immunotherapeutic approaches for PD, DLB, MSA, FTD, and other neurodegenerative disorders characterized by the abnormal accumulation of these proteins [24,26,[55][56][57][58].…”

Domain a’ of protein disulfide isomerase plays key role in inhibiting α-synuclein fibril formation

“…αSyn, initially identified as a synaptic vesicle-associated protein, is also found in the cytosol and nucleus (Kontopoulos et al 2006;Lee et al 2005). In immunogold electron microscopy examination of rat brain neurons, the αSyn concentration was found to be higher in endoplasmic reticulum (ER) than in cytoplasmic region (Zhang et al 2008).…”

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

“…α-synuclein secretion appears to be mediated by an unconventional mechanism, independent of the ER/Golgi [61,62]. Evidence suggests that this secretion is an active process as it is temperature sensitive, independent of cell death, and the amount of α-synuclein released from cells does not correlate with the release of other cytosolic proteins into the media [62].…”