Mutations in the fused in sarcoma/translocated in liposarcoma (FUS/TLS) gene have been associated with amyotrophic lateral sclerosis (ALS). FUS-positive neuropathology is reported in a range of neurodegenerative diseases, including ALS and fronto-temporal lobar degeneration with ubiquitin-positive pathology (FTLDU). To examine protein aggregation and cytotoxicity, we expressed human FUS protein in yeast. Expression of either wild type or ALS-associated R524S or P525L mutant FUS in yeast cells led to formation of aggregates and cytotoxicity, with the two ALS mutants showing increased cytotoxicity. Therefore, yeast cells expressing human FUS protein recapitulate key features of FUS-positive neurodegenerative diseases. Interestingly, a significant fraction of FUS expressing yeast cells stained by propidium iodide were without detectable protein aggregates, suggesting that membrane impairment and cellular damage caused by FUS expression may occur before protein aggregates become microscopically detectable and that aggregate formation might protect cells from FUS-mediated cytotoxicity. The N-terminus of FUS, containing the QGSY and G rich regions, is sufficient for the formation of aggregates but not cytotoxicity. The C-terminal domain, which contains a cluster of mutations, did not show aggregation or cytotoxicity. Similar to TDP-43 when expressed in yeast, FUS protein has the intrinsic property of forming aggregates in the absence of other human proteins. On the other hand, the aggregates formed by FUS are thioflavin T-positive and resistant to 0.5% sarkosyl, unlike TDP-43 when expressed in yeast cells. Furthermore, TDP-43 and FUS display distinct domain requirements in aggregate formation and cytotoxicity.
Amino Acid Sequence ; Amino Acid Substitution ; DNA-Binding Proteins ; genetics ; metabolism ; Humans ; Mutation ; Neurodegenerative Diseases ; pathology ; Protein Structure, Tertiary ; RNA-Binding Protein FUS ; chemistry ; genetics ; metabolism ; Recombinant Proteins ; genetics ; metabolism ; toxicity ; Saccharomyces cerevisiae ; growth & development ; metabolism ; Sarcosine ; analogs & derivatives ; pharmacology ; Thiazoles ; metabolism

　　Chronic kidney disease (CKD) has recently been reported to be an independent risk factor for stroke. However, a detailed analysis was yet to be conducted according to stroke subtype. We attempted to determine the risk factors for stroke using data from the “specific health checkup” for metabolic syndrome conducted by the 9 hospitals affiliated with the Akita Prefectural Federation of Agricultural Cooperatives, and evaluate and determine the risk factors for stroke. There were 401 patients who had undergone metabolic syndrome checkups from 2007 and 2010 and suffered from stroke afterwards within 3 years after the screening. The controls were all 69,407 subjects who were screened during the same period. The predictors examined were sex, age, blood pressure, BMI, cholesterol values (HDL・LDL), history of diabetes mellitus, presence of atrial fibrillation, CKD, and drinking and smoking habits. Analysis was conducted using logistic regression. The risk factors for stroke as a whole were male sex, age, blood pressure, diabetes, atrial fibrillation, CKD, and smoking history. For cerebral infarction, the risk factors were male sex, age, blood pressure, diabetes, atrial fibrillation, CKD, and smoking habit. The risk factors for cerebral hemorrhage were age, blood pressure, and CKD. For subarachnoid hemorrhage, the risk factors were female sex, age, blood pressure, low HDLemia, and CKD. In conclusion, CKD is an independent risk factor for the 3 subtypes of stroke, and in particular plays an important role as a higher risk factor for cerebral hemorrhage. Smoking cessation and controls of blood pressure, diabetes and atrial fibrillation are the important measures for stroke prevention. In addition, the further intervention should also be targeted to those with the result of CKD revealed by specific health checkups.

Mutations in the Fused in sarcoma/Translated in liposarcoma gene (FUS/TLS, FUS) have been identified among patients with amyotrophic lateral sclerosis (ALS). FUS protein aggregation is a major pathological hallmark of FUS proteinopathy, a group of neurodegenerative diseases characterized by FUS-immunoreactive inclusion bodies. We prepared transgenic Drosophila expressing either the wild type (Wt) or ALS-mutant human FUS protein (hFUS) using the UAS-Gal4 system. When expressing Wt, R524S or P525L mutant FUS in photoreceptors, mushroom bodies (MBs) or motor neurons (MNs), transgenic flies show age-dependent progressive neural damages, including axonal loss in MB neurons, morphological changes and functional impairment in MNs. The transgenic flies expressing the hFUS gene recapitulate key features of FUS proteinopathy, representing the first stable animal model for this group of devastating diseases.
Aged ; Aging ; genetics ; metabolism ; pathology ; Amyotrophic Lateral Sclerosis ; genetics ; metabolism ; pathology ; Animals ; Animals, Genetically Modified ; Disease Models, Animal ; Drosophila melanogaster ; genetics ; metabolism ; Gene Expression ; Humans ; Microscopy, Electron, Scanning ; Motor Neurons ; metabolism ; pathology ; Mushroom Bodies ; metabolism ; pathology ; Mutant Proteins ; genetics ; metabolism ; Mutation ; Photoreceptor Cells, Invertebrate ; metabolism ; pathology ; Plasmids ; RNA-Binding Protein FUS ; genetics ; metabolism ; Recombinant Fusion Proteins ; genetics ; metabolism ; Retinal Degeneration ; pathology ; physiopathology ; Transfection

BACKGROUND: We aimed to estimate the prevalence of depressive symptoms as well as suicide-related ideation among Japanese university students during the stay-home order necessitated by the coronavirus disease 2019 pandemic in Japan, and offer evidence in support of future intervention to depression and suicide prevention strategies among college and university students. METHODS: The data for this cross-sectional study were derived from the Student Mental Health Survey conducted from May 20 to June 16, 2020 at a national university in Akita prefecture. Among the 5111 students recruited, 2712 participated in this study (response rate, 53%; mean age ± standard deviation, 20.5 ±3.5 years; men, 53.8%). Depressive symptoms were identified by using the Patient Health Questionnaire-9 (PHQ-9). RESULTS: The prevalence of moderate depressive symptoms based on a PHQ-9 score ≥10 and suicide-related ideation based on question 9 of PHQ-9 ≥1, which encompasses thoughts of both suicide and self-harm, was 11.7% and 6.7%, respectively. Multivariable logistic regression analyses showed that risk factors for depression included being a woman, smoking, alcohol consumption, and social network communication using either video or voice. For suicide-related ideation, alcohol consumption was the only risk factor. Exercise and having someone to consult about worries were associated with decreased risk of both depressive symptoms and suicide-related ideation. CONCLUSIONS Negative lifestyles of smoking and drinking, and being a woman, may be important risk factors for depressive symptoms, whereas exercise and having someone to consult about worries may be protective factors.
Adolescent ; Alcohol Drinking ; COVID-19/psychology* ; Cross-Sectional Studies ; Depression/epidemiology* ; Female ; Humans ; Japan/epidemiology* ; Logistic Models ; Male ; Multivariate Analysis ; Pandemics ; Risk Factors ; Smoking ; Students/psychology* ; Suicidal Ideation ; Surveys and Questionnaires ; Young Adult