Abstract
The role of mitochondria in Parkinson’s disease (PD) has been investigated since the 1980s and is gaining attention with recent advances in PD genetics research. Mutations in PRKN and PTEN-Induced Putative Kinase 1 (PINK1) are well-established causes of autosomal recessive early-onset PD. Genetic and biochemical studies have revealed that PINK1 and Parkin proteins function together in the same biological pathway to govern mitochondrial quality control. These proteins have also been implicated in the regulation of innate and adaptive immunity and other mitochondrial functions. Additionally, structural studies on Parkin have delineated an activation mechanism and have identified druggable regions that are currently being explored by academic and industry groups. To de-risk therapeutic development for these genetic targets, The Michael J. Fox Foundation for Parkinson’s Research (MJFF) has deployed a strategic funding and enabling framework that brings together the research community to discuss important breakthroughs and challenges in research on PINK1-Parkin biology, supports collaborative initiatives to further our understanding within this field and develops high-quality research tools and assays that are widely available to all researchers. The Foundation’s efforts are leading to significant advances in understanding of the underlying biology of these genes, proteins and pathways and in the development of Parkinson’s therapies.
Highlights
Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra (SN) leading to motor dysfunction but can impact other pathways implicated in non-motor disease manifestations [1]
The etiology of PD remains largely unknown; genetic studies over the past two decades point to crucial roles for certain genes as contributors to disease onset and progression. These genetic differences are only associated with a small proportion of PD cases, they can reveal the importance of certain cellular pathways and processes that may be disrupted in PD more broadly
As therapeutic programs for PINK1 and Parkin are targeted for the idiopathic PD (iPD) population, efforts to determine if these pathways are deregulated in human samples from PINK1 and PRKN mutation carriers need to be extended to iPD subjects to identify a subset of the iPD population with similar mitochondrial phenotypes
Summary
Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra (SN) leading to motor dysfunction but can impact other pathways implicated in non-motor disease manifestations [1]. MJFF-funded researchers have identified endogenous protein substrates for LRRK2 [7], built improved models of the functional structure of the LRRK2 protein [8,9], clarified understanding of the impact of inhibiting LRRK2 kinase activity in preclinical models [10] and demonstrated that increased kinase activity is found in the idiopathic PD (iPD) population [11,12] These and other crucial data have increased confidence for continued clinical development of LRRK2-targeted therapies, the first of which are in Phase 1 clinical trials [NCT03710707 and NCT03976349]. We briefly describe the rationale for targeting these proteins and our perspective on the biological, therapeutic, biomarker and resource needs critical for successful translation of these proteins into therapies for people with PD
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