Intravesicular Localization and Exocytosis of α-Synuclein and its Aggregates

By He‐Jin Lee, Smita Patel, Seung-Jae Lee. Journal of Neuroscience, 2005

812 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/04e9b57e75b0590b69f6af91b9f9de340b49af17

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In Cell Biology

1. Leonidas Stefanis
2. M. Wood
3. P. Brundin

In Neurology

1. Leonidas Stefanis
2. Christian Haass
3. A. Lutz
4. K. Winklhofer
5. Nicole Exner
6. T. Joh
7. E. Masliah
8. A. Schapira

Citations in the corpus

• Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. (2015, background): “Mostly intracellular fraction of a synuclein fibril is released from neurons [139].”
• Cell-Produced α-Synuclein Is Secreted in a Calcium-Dependent Manner by Exosomes and Impacts Neuronal Survival (2010, background): “Indeed, part of intracellular -synuclein was found previously to be localized in secretory vesicles (Lee et al., 2005).”
• Role of Oxidative Stress in Parkinson's Disease (2013, background): “Although mostly intracellular, a fraction of α-synuclein fibril is released from neurons [41], and α-synuclein is found in the cerebrospinal fluid from PD patients and normal subjects [42], and in human plasma [43].”
• α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. (2011, positive): “Additionally, α -syn monomers and aggregates can be released from cultured cells by exocytosis (20, 23) and exosomes have been suggested to participate in this process (24).”
• α-Synuclein in Parkinson's disease. (2012, background): “The mechanism of a-synuclein secretion is not well understood, but it appears to occur through a nonclassical secretory pathway (Lee et al. 2005), possibly within exosomes, endocytic vesicles that are contained within multivesicular bodies and are released on calcium influx (Emmanouilidou et al.…”
• Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease (2006, background): “Interestingly, the intravesicular -synuclein has increased aggregation tendency, secretion of both monomeric and aggregated -synuclein is elevated in response to proteasomal and mitochondrial dysfunction (Lee et al., 2005).”
• Oxidative stress, mitochondrial damage and neurodegenerative diseases (2013, background): “Loss-of-function mutations in the gene encoding parkin cause mitochondrial dysfunction [97] and the recessively inherited form of PD [98] .”
• Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission (2011, result): “The release of alpha-synuclein from cells via exocytosis has been previously reported in SH-SY5Y cells overexpressing human alpha-synuclein (Lee et al., 2005) and associated with membrane vesicles whose identity is compatible with exosomes (Emmanoulidou et al., 2010), and we have confirmed this…”
• Exosomal cell-to-cell transmission of alpha synuclein oligomers (2012, background): “Increasing evidence suggests that αsyn can be released by neurons and neuronal like cells [17,31-33] although extracellular αsyn and its pathological relevance are still hotly debated in the field.”
• Prion-like transmission of protein aggregates in neurodegenerative diseases (2010, background): “Cultured neuroblastoma cells and neurons secrete α-synuclein monomers and aggregates by a non-classical vesicle-mediated exocytic mechanism; however, the molecular details are still unknow”
• Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences (2012, positive): “Obviously, a -synuclein is secreted from cultured cells by exocytotic vesicles (Lee et al , 2005; Jang et al , 2010) or via exosomes, which are endosome-derived vesicles secreted during fusion of multivesicular bodies with the plasma membrane (Emmanouilidou et al , 2010; Alvarez-Erviti et al ,…”
• A new pathway for mitochondrial quality control: mitochondrial‐derived vesicles (2014, positive): “Secretion and cell-to-cell transfer of a-synuclein has been shown both in cells and in vivo (Lee et al, 2004, 2005, 2008a,b; Desplats et al, 2009; Luk et al, 2012a,b), and exosomes constitute a proposed method of propagation (Emmanouilidou et al, 2010; Kong et al, 2014; Lee et al, 2014).”
• Different Species of α-Synuclein Oligomers Induce Calcium Influx and Seeding (2007, background): “Effects of extracellular oligomers on cells might play an important role, also under pathophysiological conditions, because intriguing findings have shown previously that -syn aggregates could be secreted from cells and therefore possibly insult neighboring cells (Lee et al., 2005).”
• Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein (2009, background): “We previously have found that a small but significant proportion of -synuclein and its aggregates are secreted from neuronal cells via exocytosis (13).”