Induction of Neuronal Cell Death by Rab5A-dependent Endocytosis of α-Synuclein

Sung, Jee Young; Kim, Jongsun; Paik, Seung R.; Park, Jeon Han; Ahn, Young Soo; Chung, Kwang Chul

doi:10.1074/jbc.m101318200

Cited by 183 publications

(180 citation statements)

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“…(b) Entry of a-syn into the recipient cell. Passive diffusion through the plasma membrane, 11,68 endocytosis, 9,11,12,16 and exosome-mediated transfer of a-syn into a recipient cell 14,54 have been reported. Whether an unknown receptor or lipid rafts are involved in a-syn endocytotic uptake remains to be elucidated.…”

Section: Molecular Mechanisms Involved In Intercellular Transfer Of Amentioning

confidence: 99%

“…[6][7][8] Furthermore, overexpressed and/or misfolded a-syn is pathogenic to cells while a-syn can be secreted from cells, enter other cells, and seed small intracellular aggregates, demonstrating a connection between a-syn and pathogenic mechanisms of PD. [9][10][11][12][13][14][15][16] In parallel, a much-discussed hypothesis by Braak and colleagues 17 states that a pathogenic agent, introduced via ingestion and/or inhalation, may transfer from the entry site along known long, unmyelinated axons to basal brain areas and eventually to brain stem and cortical regions. Although a-syn is unlikely to be this initial pathogen, it might be the initial target of the unknown agent.…”

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confidence: 98%

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A deadly spread: cellular mechanisms of α-synuclein transfer

2011

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Classically, Parkinson's disease (PD) is linked to dopamine neuron death in the substantia nigra pars compacta. Intracytoplasmic protein inclusions named Lewy bodies, and corresponding Lewy neurites found in neuronal processes, are also key features of the degenerative process in the substantia nigra. The molecular mechanisms by which substantia nigra dopamine neurons die and whether the Lewy pathology is directly involved in the cell death pathway are open questions. More recently, it has become apparent that Lewy pathology gradually involves greater parts of the PD brain and is widespread in late stages. In this review, we first discuss the role of misfolded a-synuclein protein, which is the main constituent of Lewy bodies, in the pathogenesis of PD. We then describe recent evidence that a-synuclein might transfer between cells in PD brains. We discuss in detail the possible molecular mechanisms underlying the proposed propagation and the likely consequences for cells that take up a-synuclein. Finally, we focus on aspects of the pathogenic process that could be targeted with new pharmaceutical therapies or used to develop biomarkers for early PD detection. Multiple hypotheses exist to help explain dopamine neuron cell death and Lewy body formation observed in Parkinson's disease (PD). Mutations of the main proteinaceous constituent of Lewy bodies, a-synuclein (a-syn), lead to dominant, familial disease forms. [1][2][3][4][5] More recently, genome-wide association studies (GWASs) identified variants of the a-synuclein gene (SNCA) gene, encoding a-syn protein, that are coupled to increased PD susceptibility, thus clearly linking this protein to idiopathic PD. 6-8 Furthermore, overexpressed and/or misfolded a-syn is pathogenic to cells while a-syn can be secreted from cells, enter other cells, and seed small intracellular aggregates, demonstrating a connection between a-syn and pathogenic mechanisms of PD. [9][10][11][12][13][14][15][16] In parallel, a much-discussed hypothesis by Braak and colleagues 17 states that a pathogenic agent, introduced via ingestion and/or inhalation, may transfer from the entry site along known long, unmyelinated axons to basal brain areas and eventually to brain stem and cortical regions. Although a-syn is unlikely to be this initial pathogen, it might be the initial target of the unknown agent. If a-syn is misfolded because of the action of the unknown agent, it might contribute to the spreading of pathology by moving from one cell to another and triggering misfolding in the recipient cells. If so, it might explain the surprising presence of Lewy bodies in the young neural grafts of transplanted PD patients observed more than a decade after surgery. [18][19][20][21] In this review, we discuss possible mechanisms by which a-syn could spread between cells and have deadly consequences by describing the molecular evidence for a-syn cellular exit, transit to other cells, uptake by cells, intracellular aggregation, and responses to a-syn accumulation.The Relationship Between a-Syn and PD ...

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Section: Molecular Mechanisms Involved In Intercellular Transfer Of Amentioning

confidence: 99%

mentioning

confidence: 98%

A deadly spread: cellular mechanisms of α-synuclein transfer

2011

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“…Suspeita-se que a α-sinucleína pré-sináptica seja a principal envolvida na formação desses corpús-culos, sendo fatores genéticos e/ou epigenéticos os possíveis responsáveis pelo surgimento dos CL nos neurônios (Sung et al, 2001;Trojanowaski e Lee, 1998). Os CL, além de representarem neurônios que sofreram degeneração, possivelmente exercem efeito neurotóxico regional.…”

Section: Etiopatogênese E Achados Neuropatológicosunclassified

Demência com corpos de Lewy: uma revisão para o psiquiatra

Tavares

Azeredo

2003

Rev. psiquiatr. clín.

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A demência com corpos de Lewy (DCL) tornou-se hoje uma entidade nosológica distinta, considerada por muitos autores a segunda causa principal de demência degenerativa, atrás apenas da doença de Alzheimer. Sua neuropatologia é caracterizada pela presença de corpos de Lewy tanto em regiões corticais como em áreas subcorticais do encéfalo. As principais manifestações clínicas incluem: declínio cognitivo progressivo, alucinações visuais recorrentes, flutuação no estado cognitivo e sinais parkinsonianos. Observa-se maior sensibilidade a efeitos indesejáveis de medicamentos neurolépticos e a resposta a medicações inibidoras da acetilcolinesterase é geralmente boa. Unitermos: Demência com corpos de Lewy; Doença de Alzheimer; Neurolépticos; Alucinações. ABSTRACT Dementia with Lewy bodies: a review for psychiatristsLewy body dementia became today a distinct nosological entity, considered by many authors the second cause of degenerative dementia, after Alzheimer's disease. Its neuropathology is caracterized by the presence of Lewy bodies both in cortical and subcortical areas of the brain. The main clinical manifestations are: progressive cognitive impairment, recurrent visual hallucinations, fluctuating cognitive status and parkinsonian signs. There is greater sensitivity to side effects of neuroleptic drugs and the response to cholinesterase inhibitors is generally good.

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“…[15][16][17][18] Although the exact mechanism of α-syn uptake has not been established, 11-amino acid imperfect repeats found in the α-syn sequence have been shown to be critical. 16 α-Syn has been shown to be internalized via GM1 and hitherto unknown protein receptors via a lipid raft-dependent endocytosis mechanism, 18 suggesting that cytosolic α-syn can be released from cells and taken up by other cells.…”

Section: Proteolytic Clearance As a Therapeutic Approach Against Pd Amentioning

confidence: 99%

“…16 α-Syn has been shown to be internalized via GM1 and hitherto unknown protein receptors via a lipid raft-dependent endocytosis mechanism, 18 suggesting that cytosolic α-syn can be released from cells and taken up by other cells. In addition to studies of its release and uptake, extracellular α-syn has been reported to have effects on neurotoxicity 15,19,20 and inflammation. 14,18,[21][22][23][24] Recent observations that the transplants grafted into the brain of PD patients displayed Lewy bodies 25,26 were considered to be connected with Braak et al's proposal that Lewy body pathology spreads from one brain area to another according to a stereotypic pattern in specific stages.…”

Section: Proteolytic Clearance As a Therapeutic Approach Against Pd Amentioning

confidence: 99%