Dr F Giorgini
University of Leicester
DJ-1 and neurodegeneration: its roles in mitochondria and in protein misfolding
Parkinson's disease & PD-related disorders|Alzheimer's disease & other dementias
Parkinson’s disease (PD), the second most common neurodegenerative disorder, presents with loss of dopaminergic neurons and the accumulation of misfolded alpha-synuclein (aSyn) in Lewy bodies. The study of genes associated with familial PD – such as PARK7 which encodes for DJ-1 – is elucidating the mechanisms underlying this disease. DJ-1 has several roles in the cell: oxidative stress sensor, protein chaperone, and a regulator of mitochondrial function. Here we seek to clarify how DJ-1 contributes to mitochondrial function and protein misfolding, and how these roles contribute to pathogenesis in PD. In initial work we have found that mutations in DJ-1 modulate its relocalization to mitochondria in mammalian cells with paraquat treatment. We thus seek to further characterize this effect with a range of disease-causing and functional mutants, additional oxidants, and in the context of aSyn expression. We also plan to investigate how DJ-1 mutations affect function and morphology of mitochondria. Finally we plan to extend this approach by studying how DJ-1 mutants modulate the structure and function of mitochondria in fruit flies. We will also explore the relationship between DJ-1 and the Tau protein, which is involved in the pathogenesis of Alzheimer’s disease (AD), is a major component of neurofibrillary tangles, and has been recently genetically linked to PD. DJ-1 modulates misfolding/toxicity of several aggregation-prone proteins and co-localizes with Tau inclusions in AD and other brain disorders. Interactions between DJ-1 and Tau have not been studied, and their relationship in the context of PD has not been explored. Thus we propose to study the interaction between DJ-1 and Tau in living mammalian cells using bimolecular fluorescence complementation, and to what extent, if any, this alters Tau toxicity or formation of fibers. We will extend this work to a fruit fly model of Tauopathies, to ascertain whether DJ-1 modulates disease-relevant phenotypes.