Genetics of Early Onset Parkinson's Disease: Mitochondrial Drivers of PD Pathogenesis

National Institute Of Neurological Disorders And Stroke

Investigators

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Abstract

Parkinsons disease (PD) represents a substantial and growing public health burden, affecting 680,000 people in the US. The cause of PD is monogenic in roughly 10% of cases, and identified genes point to targetable pathways for drug development. The most common monogenic cause of Early Onset PD (EOPD, onset 50) are loss of function (LOF) mutations in Parkin and PINK1, which affect thousands of individuals in the US. These genes not only share clinical features, but, as our work established, function in a common biological pathway to target dysfunctional mitochondria for autophagy. Interestingly, autosomal dominant mutations in CHCHD2 and its paralog CHCHD10, mitochondrial proteins of unknown function, were recently identified as also causing EOPD, underscoring a key clinical-biological correlation between EOPD and mitochondrial dysfunction. Despite substantial progress in EOPD molecular and functional genetics over the last 20 years, there remain a number of challenges for translating genetic discovery to targeted therapies for PD. The overall goal of our program is to characterize the genomic architecture, clinical phenotype, and functional genetics of EOPD to identify mitochondrial drivers of PD pathogenesis and foster targeted therapies for PD. To that end, our activities are organized around three complementary aims that draw on strengths of the intramural program and my perspective as a cell biologist and neurologist: SPECIFIC AIM 1: To determine the genomic architecture and clinical phenotype of EOPD patient cohorts (20% Effort). We have established one of the largest cohorts of PRKN mutation carriers. We have used this cohort to help define the PRKN phenotype and develop a screening framework for identifying PRKN patients for therapeutic trials, in collaboration with the Singleton lab (Zhu et al., 2021). We have also analyzed PRKN mutations in the first population scale study with near complete coverage of PRKN mutations, establishing that single pathogenic PRKN mutations are surprisingly common in the general population (found in 1.8% of individuals) but do not increase the risk of idiopathic PD (Zhu et al., 2021). We have established that the phenotype of PRKN-PD patients is distinct from other forms of early onset Parkinsons disease, such as those caused by mutations in DJ1 (Narendra et al., 2019). Additionally, in the first systematic assessment of alpha-synuclein pathology in the major forms of genetic Parkinsons disease, together with the Goldstein lab, we have established that PRKN-PD patients are unique for having low levels of alpha-synuclein pathology (Isonaka et al., 2021). SPECIFIC AIM 2: To assess novel mitochondrial drivers of neurodegeneration using model systems of genetic disorders (60% Effort). Modeling novel genetic causes of EOPD and related degenerative disorders is needed to understand their mitochondrial vulnerability and identify new targets for therapy. Generating the first CHCHD2 and CHCHD10 double knockout cell lines and animal models, we established that dominant mutations in CHCHD10 cause disease by a gain-of-function mechanism and established that CHCHD2 and CHCHCD10 are partially functionally redundant (Huang et al., 2018; Liu et al., 2020). We identified that mutations in CHCHD10 which cause protein misfolding in the intermembrane space of mitochondria disrupt the inner membrane to activate a parallel stress response to the PINK1/Parkin pathway mediated by OMA1 and OPA1 (Liu et al., 2020). SPECIFIC AIM 3: To develop novel methods for in vivo assessment of mitophagy in EOPD (20% Effort). Disrupted mitophagy is a key vulnerability in EOPD and current therapeutic target, but methods to assess mitophagy in vivo have hampered therapeutic development. To close this gap, developed new methods to monitor mitophagy that could be applied in vivo. The need for new methods was recently demonstrated in our study providing the first direct comparison of the most widely used mitophagy reporter mice, mt-Keima and the mito-QC (Liu et al., 2021). This found that while mt-Keima requires live assessment, mito-QC is less sensitive. As a complement to the fluorescent reporter-based methods, we have been developing a strategy that combines stable isotope labeling and metabolic imaging of protein turnover at the nanoscale, using NanoSIMS (Narendra et al., 2020; Narendra and Steinhauser, 2020). In a proof of principle study, we demonstrated for the first-time relative bulk protein turnover can be measured in individual organelles such as mitochondria and lysosomes (Narendra et al., 2020). We are now applying this method to mouse models with mitochondrial disease to assess mitophagy.