Non-classical exocytosis of α-synuclein is sensitive to folding states and promoted under stress conditions

Department of Anatomy, School of Medicine, Konkuk University, Seoul, Korea.
Journal of Neurochemistry (Impact Factor: 4.28). 03/2010; 113(5):1263-74. DOI: 10.1111/j.1471-4159.2010.06695.x
Source: PubMed


J. Neurochem. (2010) 113, 1263–1274.
Parkinson’s disease is characterized by deposition of misfolded/aggregated α-synuclein proteins in multiple regions of the brain. Neurons can release α-synuclein; through this release, pathological forms of α-synuclein are propagated between neurons, and also cause neuroinflammation. In this study, we demonstrate that release of α-synuclein is consistently increased under various protein misfolding stress conditions in both neuroblastoma and primary neuron models. This release is mediated by a non-classical, endoplasmic reticulum (ER)/Golgi-independent exocytosis, and stress-induced release coincides with increased translocation of α-synuclein into vesicles. Both vesicle translocation and secretion were blocked by attachment of a highly stable, globular protein to α-synuclein, whereas forced protein misfolding resulted in an increase in both of these activities. Mass spectrometry analysis showed a higher degree of oxidative modification in secreted α-synuclein than in the cellular protein. Together, these results suggest that structurally abnormal, damaged α-synuclein proteins translocate preferentially into vesicles and are released from neuronal cells via exocytosis.

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Available from: Kwang pyo kim, Jan 27, 2015
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    • "Regarding PD and toxicity of ␣-syn, widespread ␣-syn plaque pathology in absence of neurodegeneration has also been recently reported (Masuda-Suzukake et al., 2013) and association of oligomers with toxicity was shown in cell culture models as well (Danzer et al., 2007, 2011; Emmanouilidou et al., 2010). The relationship with UPR has been observed since the ␣-syn release from neurons increases during protein misfolding stress (Jang et al., 2010). Nevertheless, while the cellular model has shown that prefibrillar dimers and other small aggregates induce neurotoxicity, these results should be validated in vivo (Roostaee et al., 2013). "
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    ABSTRACT: Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are a group of fatal neurodegenerative disorders affecting several mammalian species being Creutzfeldt-Jacob Disease (CJD) the most representative in human beings, scrapie in ovine, Bovine Spongiform Encephalopathy (BSE) in bovine and Chronic Wasting Disease (CWD) in cervids. As stated by the "protein-only hypothesis", the causal agent of TSEs is a self-propagating aberrant form of the prion protein (PrP) that through a misfolding event acquires a β-sheet rich conformation known as PrP(Sc) (from scrapie). This isoform is neurotoxic, aggregation prone and induces misfolding of native cellular PrP. Compelling evidence indicates that disease-specific protein misfolding in amyloid deposits could be shared by other disorders showing aberrant protein aggregates such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic lateral sclerosis (ALS) and systemic Amyloid A amyloidosis (AA amyloidosis). Evidences of shared mechanisms of the proteins related to each disease with prions will be reviewed through the available in vivo models. Taking prion research as reference, typical prion-like features such as seeding and propagation ability, neurotoxic species causing disease, infectivity, transmission barrier and strain evidences will be analyzed for other protein-related diseases. Thus, prion-like features of amyloid β peptide and tau present in AD, α-synuclein in PD, SOD-1, TDP-43 and others in ALS and serum α-amyloid (SAA) in systemic AA amyloidosis will be reviewed through models available for each disease. Copyright © 2015. Published by Elsevier B.V.
    Virus Research 04/2015; 207. DOI:10.1016/j.virusres.2015.04.014 · 2.32 Impact Factor
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    • "Alpha-synuclein (Snca) is the major protein constituent of Lewy bodies (Spillantini et al., 1998). Snca is mainly a cytoplasmic protein, but it has been shown to be secreted by exocytosis and is also present in exosomes (Lee et al., 2005; Emmanouilidou et al., 2010; Jang et al., 2010; Pan-Montojo et al., 2012). Snca has been found in cerebrospinal fluid (CSF) and plasma and its concentration in these fluids has been suggested as a possible biomarker for PD (Parnetti et al., 2013), even though there are substantial discrepancies between the results reported in different studies (Lee et al., 2006; Li et al., 2007; Duran et al., 2010; Shi et al., 2010; Mollenhauer et al., 2011; Park et al., 2011; Foulds et al., 2012; Wennstrom et al., 2013). "
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    ABSTRACT: Alpha-synuclein (Snca) plays a major role in Parkinson disease (PD). Circulating anti-Snca antibodies has been described in PD patients and healthy controls, but they have been poorly characterized. This study was designed to assess the prevalence of anti-Snca reactivity in human subjects carrying the LRRK2 mutation, idiopathic PD (iPD) patients, and healthy controls and to map the epitopes of the anti-Snca antibodies. Antibodies to Snca were detected by ELISA and immunoblotting using purified recombinant Snca in plasma from individuals carrying LRRK2 mutations (104), iPD patients (59), and healthy controls (83). Epitopes of antibodies were mapped using recombinant protein constructs comprising different regions of Snca. Clear positive anti-Snca reactivity showed no correlation with age, sex, years of evolution, or the disability scores for PD patients and anti-Snca reactivity was not prevalent in human patients with other neurological or autoimmune diseases. Thirteen of the positive individuals were carriers of LRRK2 mutations either non-manifesting (8 out 49 screened) or manifesting (5 positive out 55), three positive (out of 59) were iPD patients, and five positive (out of 83) were healthy controls. Epitope mapping showed that antibodies against the N-terminal (a.a. 1-60) or C-terminal (a.a. 109-140) regions of Snca predominate in LRRK2 mutation carriers and iPD patients, being N122 a critical amino acid for recognition by the anti-C-terminal directed antibodies. Anti-Snca circulating antibodies seem to cluster within families carrying the LRRK2 mutation indicating possible genetic or common environmental factors in the generation of anti-Snca antibodies. These results suggest that case-controls' studies are insufficient and further studies in family cohorts of patients and healthy controls should be undertaken, to progress in the understanding of the possible relationship of anti-Snca antibodies and PD pathology.
    Frontiers in Aging Neuroscience 07/2014; 6:169. DOI:10.3389/fnagi.2014.00169 · 4.00 Impact Factor
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    • "Like AD, microglial activation and subsequent over-production of inflammatory mediators have been suggested to be responsible for the neurodegeneration [51]. Studies suggest that misfolding and aggregation of α-synuclein proteins can lead to its release from neurons [52], and subsequently induce inflammatory responses from glial cells [53], yet the molecular mechanism has not been defined. In collaboration with our group, Kim et al. have investigated the role of TLR2 in α-synuclein-induced microglial activation [54]. "
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    ABSTRACT: Toll-like receptors (TLRs) belong to a class of pattern recognition receptors that play an important role in host defense against pathogens. TLRs on innate immune cells recognize a wide variety of pathogen-associated molecular patterns (PAMPs) and trigger innate immune responses. Later, it was revealed that the same receptors are also utilized to detect tissue damage to trigger inflammatory responses in the context of non-infectious inflammation. In the nervous system, different members of the TLR family are expressed on glial cells including astrocytes, microglia, oligodendrocytes, and Schwann cells, implicating their putative role in innate/inflammatory responses in the nervous system. In this regard, we have investigated the function of TLRs in neuroinflammation. We discovered that a specific member of the TLR family, namely TLR2, functions as a master sentry receptor to detect neuronal cell death and tissue damage in many different neurological conditions including nerve transection injury, intracerebral hemorrhage, traumatic brain injury, and hippocampal excitotoxicity. In this review, we have summarized our research for the last decade on the role of TLR2 in neuroinflammation in the above neurological disorders. Our data suggest that TLR2 can be an efficient target to regulate unwanted inflammatory response in these neurological conditions.
    06/2014; 23(2):138-47. DOI:10.5607/en.2014.23.2.138
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