Alpha-synuclein transmission and mitochondrial toxicity in primary human foetal enteric neurons in vitro

Nady Braidy, Wei Ping Gai, Ying Hua Xu, Perminder Sachdev, Gilles J. Guillemin, Xing Mai Jiang, J. William O Ballard, Martin P. Horan, Zhi Ming Fang, Beng H. Chong, Daniel Kam Yin Chan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)170-182
Number of pages13
JournalNeurotoxicity Research
Volume25
Issue number2
DOIs
Publication statusPublished - Feb 2014
Externally publishedYes

Keywords

  • Alpha-synuclein
  • Endocytosis
  • Mitochondria
  • Parkinson's disease

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