title: Alpha-synuclein transmission and mitochondrial toxicity in primary human foetal enteric neurons in vitro.
abstract: Parkinson's disease (PD) is a multicentred neurodegenerative disorder characterised by the accumulation and aggregation of alpha-synuclein (α-syn) in several parts of the central nervous system. However, it is well established that PD can generate symptoms of constipation and other gastrointestinal problems and α-syn containing lesions have been identified in intestinal nerve cells. In this study, we show that α-syn can be taken up and accumulate in primary human foetal enteric neurons from the gastrointestinal tract and can be transferred between foetal enteric neurons. Impaired proteosomal/lysosomal degradation can promote the uptake and accumulation of α-syn in enteric neurons. Enteric neurons exposed to α-syn can also lead to impaired mitochondrial complex I activity, reduced mitochondrial function, and NAD(+) depletion culminating in cell death via energy restriction. These findings demonstrate neuron-to-neuron transmission of α-syn in enteric neurons, providing renewed evidence for Braak's hypothesis and the aetiology of PD.
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia, n.braidy@unsw.edu.au.
authors.forename: Nady
authors.initials: N
authors.lastname: Braidy
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Gai
authors.forename: Ying Hua
authors.initials: YH
authors.lastname: Xu
authors.forename: Perminder
authors.initials: P
authors.lastname: Sachdev
authors.forename: Gilles J
authors.initials: GJ
authors.lastname: Guillemin
authors.forename: Xing-Mai
authors.initials: XM
authors.lastname: Jiang
authors.forename: J William O
authors.initials: JW
authors.lastname: Ballard
authors.forename: Martin P
authors.initials: MP
authors.lastname: Horan
authors.forename: Zhi Ming
authors.initials: ZM
authors.lastname: Fang
authors.forename: Beng H
authors.initials: BH
authors.lastname: Chong
authors.forename: Daniel Kam Yin
authors.initials: DK
authors.lastname: Chan
mesh_terms: D002478:Cells, Cultured; D004705:Endocytosis; D017615:Enteric Nervous System / Q000187:drug effects* / Q000378:metabolism; D005333:Fetus; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism / Q000633:toxicity*
chemical_list: D051844:alpha-Synuclein
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