Rotenone and elevated extracellular potassium concentration induce cell-specific fibrillation of a-synuclein in axons of cholinergic enteric neurons in the guinea-pig ileum

Dale Sharrad, Bao Chen, Wei-Ping Gai, N Vaikath, O El-Agnaf, Simon Brookes

    Research output: Contribution to journalArticlepeer-review

    9 Citations (Scopus)

    Abstract

    Background: Parkinson's disease is a progressive neurodegenerative disorder that results in the widespread loss of select classes of neurons throughout the nervous system. The pathological hallmarks of Parkinson's disease are Lewy bodies and neurites, of which α-synuclein fibrils are the major component. α-Synuclein aggregation has been reported in the gut of Parkinson's disease patients, even up to a decade before motor symptoms, and similar observations have been made in animal models of disease. However, unlike the central nervous system, the nature of α-synuclein species that form these aggregates and the classes of neurons affected in the gut are unclear. We have previously reported selective expression of α-synuclein in cholinergic neurons in the gut (J Comp Neurol. 2013; 521:657), suggesting they may be particularly vulnerable to degeneration in Parkinson's disease. Methods: In this study, we used immunohistochemistry to detect α-synuclein oligomers and fibrils via conformation-specific antibodies after rotenone treatment or prolonged exposure to high [K+] in ex vivo segments of guinea-pig ileum maintained in organotypic culture. Key Results: Rotenone and prolonged raising of [K+] caused accumulation of α-synuclein fibrils in the axons of cholinergic enteric neurons. This took place in a time- and, in the case of rotenone, concentration-dependent manner. Rotenone also caused selective necrosis, indicated by increased cellular autofluorescence, of cholinergic enteric neurons, labeled by ChAT-immunoreactivity, also in a concentration-dependent manner. Conclusions & Inferences: To our knowledge, this is the first report of rotenone causing selective loss of a neurochemical class in the enteric nervous system. Cholinergic enteric neurons may be particularly susceptible to Lewy pathology and degeneration in Parkinson's disease.

    Original languageEnglish
    Article numbere12985
    Pages (from-to)Art: e12985
    Number of pages19
    JournalNeurogastroenterology and Motility
    Volume29
    Issue number4
    DOIs
    Publication statusPublished - 2017

    Fingerprint Dive into the research topics of 'Rotenone and elevated extracellular potassium concentration induce cell-specific fibrillation of a-synuclein in axons of cholinergic enteric neurons in the guinea-pig ileum'. Together they form a unique fingerprint.

    Cite this