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Background: Most Parkinson's disease (PD) loci have shown low prevalence in the Indian population, highlighting the need for further research. Objective: The aim of this study was to characterize a novel phosphatase tensin homolog‐induced serine/threonine kinase 1 (PINK1) mutation causing PD in an Indian family. Methods: Exome sequencing of a well‐characterized Indian family with PD. A novel PINK1 mutation was studied by in silico modeling using AlphaFold2, expression of mutant PINK1 in human cells depleted of functional endogenous PINK1, followed by quantitative image analysis and biochemical assessment. Results: We identified a homozygous chr1:20648535–20648535 T>C on GRCh38 (p.F385S) mutation in exon 6 of PINK1, which was absent in 1029 genomes from India and in other known databases. PINK1 F385S lies within the highly conserved DFG motif, destabilizes its active state, and impairs phosphorylation of ubiquitin at serine 65 and proper engagement of parkin upon mitochondrial depolarization. Conclusions: We characterized a novel nonconservative mutation in the DFG motif of PINK1, which causes loss of its ubiquitin kinase activity and inhibition of mitophagy. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: A recently published East Asian genome‐wide association study of Parkinson;s disease (PD) reported 2 novel risk loci, SV2C and WBSCR17. Objectives: The objective of this study were to determine whether recently reported novel SV2C and WBSCR17 loci contribute to the risk of developing PD in European and East Asian ancestry populations. Methods: We report an association analysis of recently reported variants with PD in the COURAGE‐PD cohort (9673 PD patients; 8465 controls) comprising individuals of European and East Asian ancestries. In addition, publicly available summary data (41,386 PD patients; 476,428 controls) were pooled. Results: Our findings confirmed the role of the SV2C variant in PD pathogenesis (rs246814, COURAGE‐PD PEuropean = 6.64 × 10−4, pooled PD P = 1.15 × 10−11). The WBSCR17 rs9638616 was observed as a significant risk marker in the East Asian pooled population only (P = 1.16 × 10−8). Conclusions: Our comprehensive study provides an up‐to‐date summary of recently detected novel loci in different PD populations and confirmed the role of SV2C locus as a novel risk factor for PD irrespective of the population or ethnic group analyzed. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: VPS35 is part of the retromer complex and is responsible for the trafficking and recycling of proteins implicated in autophagy and lysosomal degradation, but also takes part in the degradation of mitochondrial proteins via mitochondria‐derived vesicles. The p.D620N mutation of VPS35 causes an autosomal‐dominant form of Parkinson's disease (PD), clinically representing typical PD. Objective: Most of the studies on p.D620N VPS35 were performed on human tumor cell lines, rodent models overexpressing mutant VPS35, or in patient‐derived fibroblasts. Here, based on identified target proteins, we investigated the implication of mutant VPS35 in autophagy, lysosomal degradation, and mitochondrial function in induced pluripotent stem cell‐derived neurons from a patient harboring the p.D620N mutation. Methods: We reprogrammed fibroblasts from a PD patient carrying the p.D620N mutation in the VPS35 gene and from two healthy donors in induced pluripotent stem cells. These were subsequently differentiated into neuronal precursor cells to finally generate midbrain dopaminergic neurons. Results: We observed a decreased autophagic flux and lysosomal mass associated with an accumulation of α‐synuclein in patient‐derived neurons compared to controls. Moreover, patient‐derived neurons presented a mitochondrial dysfunction with decreased membrane potential, impaired mitochondrial respiration, and increased production of reactive oxygen species associated with a defect in mitochondrial quality control via mitophagy. Conclusion: We describe for the first time the impact of the p.D620N VPS35 mutation on autophago‐lysosome pathway and mitochondrial function in stem cell‐derived neurons from an affected p.D620N carrier and define neuronal phenotypes for future pharmacological interventions. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion Parkinson's disease (PD) is the second most common, and the fastest‐growing neurodegenerative disorder with unclear etiology in most cases. Therefore, the identification of non‐genetic risk factors for PD pathology is crucial to develop effective preventative or therapeutic strategies. An increasing number of evidence suggests that central insulin resistance might have an essential role in PD pathology. Nevertheless, it is not clear whether insulin resistance arises from external factors/lifestyle, comorbidities such as type 2 diabetes or it can occur in a PD patient's brain independently from peripheral insulin resistance.We aimed to investigate insulin resistance and its role in GBA1 mutation‐associated PD pathogenesis and phenotype severity.Midbrain organoids, generated from induced pluripotent stem cells (iPSCs) of PD patients carrying the GBA1‐N370S heterozygous mutation (GBA‐PD) and healthy donors, were exposed to different insulin concentrations to modify insulin signaling function. Transcriptomics analysis was performed to explore insulin signaling gene expression patterns in GBA‐PD and to find a potential target for GBA‐PD‐associated phenotype rescue.The insulin signaling pathway genes show dysregulation in GBA‐PD. Particularly, we highlight that a knockdown of FOXO1 mitigates the loss of dopaminergic neurons and cellular death in GBA‐PD. Additionally, our findings suggest a promising therapeutic potential of the anti‐diabetic drug Pioglitazone in decreasing dopaminergic neuron loss associated with GBA‐PD.Local insulin signaling dysfunction plays a substantial role in GBA‐PD pathogenesis, exacerbating dopaminergic neuron death. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]