No abstract

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.

Purpose: Acute renal infarction is often missed or diagnosed late due to its rarity and nonspecific clinical manifestations. This study analyzed the clinical and laboratory findings of patients diagnosed with renal infarction to determine whether it affects short-or long-term renal prognosis. Methods: We retrospectively reviewed the medical records of 100 patients diagnosed as acute renal

We report on two additional cases of metformin-associated encephalopathy in patients with end-stage renal disease (ESRD) undergoing hemodialysis. Two patients were seen at our hospital with abnormal neurological signs and symptoms. Magnetic resonance imaging (MRI) revealed the same pattern of high signal intensity in both basal ganglia in T2-weighted images in the two patients. The two patients had started taking metformin 5 and 6 weeks earlier at the same dose of 1000 mg per day. Metformin was immediately stopped, and regular hemodialysis was conducted. Their signs and symptoms resolved completely after these measures. The high signal intensity in both ganglia in T2-weighted MRI also disappeared. We should suspect metformin-induced encephalopathy and withdraw the drug when presented with diabetic patients with chronic kidney disease and neurological signs and symptoms of unknown cause.

Background: The present study examined the correlations between obesity, sarcopenia, and osteoarthritis in Korea' s elderly population. Methods: A cross-sectional analysis of 1,865 and 1,769 respondents with knee osteoarthritis and lumbar spondylosis, respectively, was performed by using data from the 2010 and 2011 Korea National Health and Nutrition Examination Survey. Obesity was defined as a body mass index of ≥25 kg/m 2 ; osteoarthritis, as a Kellgren/Lawrence grade of ≥2; and sarcopenia, as an appendicular skeletal muscle mass (ASM; ASM/weight ×100) on dualenergy X-ray absorptiometry of two standard deviations below the mean reference value. Results: The unadjusted and age-adjusted risks of knee osteoarthritis were as follows: 1.88 and 1.92 times greater, respectively, for male subjects with sarcopenic obesity; 6.03 and 7.64 times greater, respectively, for female subjects with non-sarcopenic obesity; and 1.97 and 2.43 times greater, respectively, for female subjects with sarcopenic obesity. The age-and-waist circumference-adjusted risks were 5.88 and 1.80 times greater for the female subjects with non-sarcopenic and sarcopenic obesities, respectively. No statistically significant finding was obtained for lumbar spondylosis. Conclusion: Obesity and sarcopenia were associated with knee osteoarthritis in the elderly subjects. The risk of knee osteoarthritis was greater in the male subjects with sarcopenic obesity than in the male subjects with nonsarcopenic obesity. In the female subjects, the risk of knee osteoarthritis was high in both obesity groups. Further research to explain the sex-related difference in knee osteoarthritis risk based on body composition will be beneficial.

BackgroundTerlipressin, as a prodrug of vasopressin, has agonistic effects on the V1 receptor and partial agonistic effects on renal vasopressin V2 receptors. However, its effects on serum sodium concentration are controversial.MethodsThis study retrospectively investigated 127 patients with liver cirrhosis to examine the incidence and risk factors for the decrease in serum sodium level following terlipressin administration.ResultsTerlipressin was prescribed for bleeding control (99) and management of hepatorenal syndrome (28). Serum sodium level decreased from 134.0 ± 6.5 mmol/L to 130.4 ± 6.2 mmol/L during or after terlipressin treatment (P < 0.001) in all patients. In 45 patients (35.4%), the serum sodium concentration decreased by > 5 mmol/L, in 29 patients (22.8%); by 5–10 mmol/L; and in 16 patients (12.6%), by > 10 mmol/L. Five patients in the latter group showed neurological manifestations. In the univariate analysis, several factors including age, purpose of use, serum creatinine, and Model for End-Stage Liver Disease score, representing liver function, were significantly associated with the decrease in serum sodium after terlipressin administration. However, a multivariate analysis revealed that only initial sodium level was the most powerful predictor of terlipressin-induced reduction in serum sodium.ConclusionAn acute reduction in serum sodium concentration was not uncommon during terlipressin treatment, and the baseline serum sodium level was closely related to the reduction in serum sodium concentration.