Abstract

Parkinson’s disease is the second most common neurodegenerative disorder. It is characterized primarily by a movement disorder due to the preferential loss of dopaminergic neurons and accumulation of misfolded alpha-synuclein in Lewy bodies. Currently there is no cure and only partially symptomatic treatment. A major limitation in our understanding of the neurodegenerative process is the lack of models that faithfully recapitulate the human condition. To bypass this limitation, we have used two approaches in the laboratory: (i) We studied protein changes in human post-mortem brain tissue from Parkinson’s patients followed by pathway deconvolution in reductionist models such as in vitro reconstitution assays and Drosophila models and (ii) we characterized cellular phenotypes using iPSC-derived dopaminergic neurons from patients with rare mutations that phenocopy Parkinson’s disease with a view to identify new mechanisms that are also relevant to sporadic disease and normal ageing. We have demonstrated the utility of this approach in the study of two key effector pathways in Parkinson’s pathogenesis, i.e. alpha-synuclein aggregation and defective mitochondrial function. Using the reductionist approach, we found that alpha-synuclein is ubiquitinated in human brain, delineated enzymes in the ubiquitin system that regulate this post-translational modification and showed their protection function against alpha-synuclein-induced proteotoxicity.In iPSC-derived neurons from patients with mitochondrial parkinsonism due to OPA1 haploinsufficiency, we have shown that loss of OPA1 causes a progressive defect in oxidative phosphorylation and mitochondrial dynamics in human dopaminergic neurons and demonstrated how such deficits may underpin disease severity. The presentation will give an overview of these studies and discuss how we are integrating these experimental systems in the search of novel targets for future therapies