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Alpha-Synuclein Transmission and Mitochondrial Toxicity in Primary Human Foetal Enteric Neurons In Vitro

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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.

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Acknowledgments

This work was supported by the UNSW Faculty of Medicine Research Grant to Dr Nady Braidy. Dr Nady Braidy is also the recipient of an Alzheimer’s Australia Viertel Foundation and NHMRC Early Career Postdoctoral Research Grant at the University of New South Wales. This work has also been supported by the Alzheimer’s Association (Grant#IIRG-08-89545) and by the Rebecca Cooper foundation (Australia).

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Authors and Affiliations

  1. Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia

    Nady Braidy & Perminder Sachdev

  2. Aged Care and Rehabilitation Unit, Bankstown-Lidcombe Hospital, Eldridge Road, Bankstown, NSW, 2031, Australia

    Nady Braidy, Ying Hua Xu & Daniel Kam Yin Chan

  3. Department of Human Physiology and Centre for Neuroscience, Flinders University School of Medicine, Adelaide, SA, Australia

    Wei-Ping Gai

  4. Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia

    Ying Hua Xu & Daniel Kam Yin Chan

  5. Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, NSW, Australia

    Perminder Sachdev

  6. School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia

    Gilles J. Guillemin

  7. St Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia

    Gilles J. Guillemin

  8. St George Clinical School, University of New South Wales, Sydney, NSW, Australia

    Xing-Mai Jiang, Zhi Ming Fang & Beng H. Chong

  9. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia

    J. William O. Ballard & Martin P. Horan

  10. St George Hospital, Sydney, NSW, Australia

    Xing-Mai Jiang, Zhi Ming Fang & Beng H. Chong

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  1. Nady Braidy
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  11. Daniel Kam Yin Chan
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Correspondence to Daniel Kam Yin Chan.

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Braidy, N., Gai, WP., Xu, Y.H. et al. Alpha-Synuclein Transmission and Mitochondrial Toxicity in Primary Human Foetal Enteric Neurons In Vitro. Neurotox Res 25, 170–182 (2014). https://doi.org/10.1007/s12640-013-9420-5

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