Rotenone susceptibility phenotype in olfactory derived patient cells as a model of idiopathic Parkinson's disease

Murtaza, M., Shan, J., Matigian, N., Todorovic, M., Cook, A.L., Ravishankar, S., Dong, L.F., Neuzil, J., Silburn, P., Mackay-Sim, A., Mellick, G.D. and Wood, S.A. (2016) Rotenone susceptibility phenotype in olfactory derived patient cells as a model of idiopathic Parkinson's disease. PLoS ONE, 11 4: . doi:10.1371/journal.pone.0154544

Author Murtaza, M.
Shan, J.
Matigian, N.
Todorovic, M.
Cook, A.L.
Ravishankar, S.
Dong, L.F.
Neuzil, J.
Silburn, P.
Mackay-Sim, A.
Mellick, G.D.
Wood, S.A.
Title Rotenone susceptibility phenotype in olfactory derived patient cells as a model of idiopathic Parkinson's disease
Journal name PLoS ONE   Check publisher's open access policy
ISSN 1932-6203
Publication date 2016-04-28
Sub-type Article (original research)
DOI 10.1371/journal.pone.0154544
Open Access Status DOI
Volume 11
Issue 4
Total pages 19
Place of publication San Francisco, United States
Publisher Public Library of Science
Collection year 2017
Language eng
Formatted abstract
Parkinson’s disease is a complex age-related neurodegenerative disorder. Approximately 90% of Parkinson’s disease cases are idiopathic, of unknown origin. The aetiology of Parkinson’s disease is not fully understood but increasing evidence implies a failure in fundamental cellular processes including mitochondrial dysfunction and increased oxidative stress. To dissect the cellular events underlying idiopathic Parkinson’s disease, we use primary cell lines established from the olfactory mucosa of Parkinson’s disease patients. Previous metabolic and transcriptomic analyses identified deficiencies in stress response pathways in patient-derived cell lines. The aim of this study was to investigate whether these deficiencies manifested as increased susceptibility, as measured by cell viability, to a range of extrinsic stressors. We identified that patient-derived cells are more sensitive to mitochondrial complex I inhibition and hydrogen peroxide induced oxidative stress, than controls. Exposure to low levels (50 nM) of rotenone led to increased apoptosis in patient-derived cells. We identified an endogenous deficit in mitochondrial complex I in patient-derived cells, but this did not directly correlate with rotenone-sensitivity. We further characterized the sensitivity to rotenone and identified that it was partly associated with heat shock protein 27 levels. Finally, transcriptomic analysis following rotenone exposure revealed that patient-derived cells express a diminished response to rotenone-induced stress compared with cells from healthy controls. Our cellular model of idiopathic Parkinson’s disease displays a clear susceptibility phenotype to mitochondrial stress. The determination of molecular mechanisms underpinning this susceptibility may lead to the identification of biomarkers for either disease onset or progression.
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Document type: Journal Article
Sub-type: Article (original research)
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Queensland Brain Institute Publications
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