Rotenone susceptibility phenotype in olfactory derived patient cells as a model of idiopathic Parkinsonís disease
Murtaza, M and Shan, J and Matigian, N and Todorovic, M and Cook, AL and Ravishankar, S and Dong, LF and Neuzil, J and Silburn, P and Mackay-Sim, A and Mellick, GD and Wood, SA, Rotenone susceptibility phenotype in olfactory derived patient cells as a model of idiopathic Parkinson's disease, PloS One, 11, (4) Article e0154544. ISSN 1932-6203 (2016) [Refereed Article]
Copyright 2016 Murtaza et al.
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Parkinsonís disease is a complex age-related neurodegenerative disorder. Approximately 90% of Parkinsonís disease cases are idiopathic, of unknown origin. The aetiology of Parkinsonís 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 Parkinsonís disease, we use primary cell lines established from the olfactory mucosa of Parkinsonís 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 Parkinsonís 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.