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Propagation of α-synuclein aggregates has been suggested as a contributing factor in Parkinson’s disease (PD) progression. However, the molecular mechanisms underlying α-synuclein aggregation are not fully understood. Here, we demonstrate in cell culture, nematode, and rodent models of PD that leucine-rich repeat kinase 2 (LRRK2), a PD-linked kinase, modulates α-synuclein propagation in a kinase activity-dependent manner. The PD-linked G2019S mutation in LRRK2, which increases kinase activity, enhances propagation efficiency. Furthermore, we show that the role of LRRK2 in α-synuclein propagation is mediated by RAB35 phosphorylation. Constitutive activation of RAB35 overrides the reduced α-synuclein propagation phenotype in lrk-1 mutant C. elegans. Finally, in a mouse model of synucleinopathy, administration of an LRRK2 kinase inhibitor reduced α-synuclein aggregation via enhanced interaction of α-synuclein with the lysosomal degradation pathway. These results suggest that LRRK2-mediated RAB35 phosphorylation is a potential therapeutic target for modifying disease progression.

BackgroundSarcopenia is associated with metabolic disorders, cardiovascular disease, and mortality; however, its association with depression in the general population remains unknown. Therefore, we investigated this association in Korea.MethodsThis study included 8,958 and 8,518 subjects from the 2010–2011 Korean National Health and Nutrition Examination Survey V-1, 2. The study was restricted to participants ≥20 years of age who had completed the survey, including whole-body dual-energy X-ray absorptiometry scans. After exclusion, 7,364 subjects were included in our final analysis. Age was categorized into three groups (20–39, 40–59, and ≥60 years), and subjects were categorized according to their sarcopenic and obesity status. Depression was categorized into three groups (not depressed, depressed, and depression).ResultsThe sarcopenia group did not have a higher prevalence of depression or depressive symptoms compared to the nonsarcopenia group; the same was true even when obesity was considered. All age groups showed non-significant associations between sarcopenia and depression. In multivariate logistic regression models, no significant associations were observed between sarcopenia and prevalence of depression or depressed symptoms in men and women.ConclusionWe found no associations between sarcopenia and the prevalence of depression or depressed symptoms in Korean adults. Future large prospective studies and randomized controlled trials are needed to further assess this relationship.

Loss-of-function mutations of DNAJC6, encoding HSP40 auxilin, have recently been identified in patients with early-onset Parkinson’s disease (PD). To study the roles of DNAJC6 in PD pathogenesis, we used human embryonic stem cells with CRISPR-Cas9–mediated gene editing. Here, we show that DNAJC6 mutations cause key PD pathologic features, i.e., midbrain-type dopamine (mDA) neuron degeneration, pathologic α-synuclein aggregation, increase of intrinsic neuronal firing frequency, and mitochondrial and lysosomal dysfunctions in human midbrain-like organoids (hMLOs). In addition, neurodevelopmental defects were also manifested in hMLOs carrying the mutations. Transcriptomic analyses followed by experimental validation revealed that defects in DNAJC6-mediated endocytosis impair the WNT-LMX1A signal during the mDA neuron development. Furthermore, reduced LMX1A expression during development caused the generation of vulnerable mDA neurons with the pathologic manifestations. These results suggest that the human model of DNAJC6-PD recapitulates disease phenotypes and reveals mechanisms underlying disease pathology, providing a platform for assessing therapeutic interventions.