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.
Highlights
Parkinson’s disease is a complex age-related disorder, affecting approximately 2% of the population over 60 years [1]
Based on comparison of multiple patient-derived and control-derived cell lines, we identified disease-specific differences in response to cellular stress that result in increased cell apoptosis, we identified an endogenous deficit in mitochondrial complex I in idiopathic Parkinson’s disease and this may represent a point of convergence of genetic and idiopathic forms of the disease
We demonstrate that 1) Parkinson’s disease patient-derived cells are more sensitive to mitochondrial stressors but not to other cell stressors; 2) the sensitivity to rotenone is observed in cells from patients with idiopathic Parkinson’s disease as well as some genetic forms Parkinson’s disease, but not in cells from patients with other neurodegenerative diseases; 3) patient-derived cells have lower mitochondrial complex I activity and, 4) patient-derived cells have a diminished transcriptional response to rotenone exposure
Summary
Parkinson’s disease is a complex age-related disorder, affecting approximately 2% of the population over 60 years [1]. The main pathological hallmarks of Parkinson’s disease are the progressive loss of dopaminergic neurons from the pars compacta of the substantia nigra and the presence of cytoplasmic inclusions called Lewy bodies. 90% of Parkinson’s disease cases are idiopathic, of unknown origin, while 10% have a familial origin [6,7]. Extensive studies from genetic cellular and animal models of Parkinson’s disease implicate mitochondrial dysfunction, increased oxidative stress, impaired proteasomal degradation and calcium buffering as prominent contributors to the disease process and these bioenergetic deficits are not restricted to dopaminergic neurons [16,17,18,19]
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