title: Rotenone Susceptibility Phenotype in Olfactory Derived Patient Cells as a Model of Idiopathic Parkinson's Disease.
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.
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Murtaza
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Shan
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Matigian
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Todorovic
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia.|Wicking Dementia Research and Education Centre, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: A L
authors.initials: AL
authors.lastname: Cook
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Ravishankar
authors.affiliation: Apoptosis Research Group, School of Medical Science, Griffith University, Southport, Queensland, Australia.
authors.forename: L F
authors.initials: LF
authors.lastname: Dong
authors.affiliation: Apoptosis Research Group, School of Medical Science, Griffith University, Southport, Queensland, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Neuzil
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia.|Asia-Pacific Centre for Neuromodulation, University of Queensland, Brisbane, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Silburn
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Mackay-Sim
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia.
authors.forename: G D
authors.initials: GD
authors.lastname: Mellick
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia.
authors.forename: S A
authors.initials: SA
authors.lastname: Wood
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival; D002478:Cells, Cultured; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008928:Mitochondria / Q000378:metabolism*; D009831:Olfactory Mucosa / Q000166:cytology* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000209:etiology / Q000473:pathology*; D012402:Rotenone / Q000494:pharmacology*
chemical_list: D055551:HSP27 Heat-Shock Proteins; C442250:HSPB2 protein, human; D012402:Rotenone; D006861:Hydrogen Peroxide; D042967:Electron Transport Complex I