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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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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DOI: https://doi.org/10.1007/s12640-013-9420-5