Approximately 20% of familial amyotrophic lateral sclerosis (FALS) arises from germ-line mutations in the superoxide dismutase-1 (SOD1) gene. However, the molecular mechanisms underlying the process have been elusive. Here, we show that a neuronal homologous to E6AP carboxyl terminus (HECT)-type ubiquitin-protein isopeptide ligase (NEDL1) physically binds translocon-associated protein-␦ and also binds and ubiquitinates mutant (but not wild-type) SOD1 proportionately to the disease severity caused by that particular mutant. Immunohistochemically, NEDL1 is present in the central region of the Lewy body-like hyaline inclusions in the spinal cord ventral horn motor neurons of both FALS patients and mutant SOD1 transgenic mice. Two-hybrid screening for the physiological targets of NEDL1 has identified Dishevelled-1, one of the key transducers in the Wnt signaling pathway. Mutant SOD1 also interacted with Dishevelled-1 in the presence of NEDL1 and caused its dysfunction. Thus, our results suggest that an adverse interaction among misfolded SOD1, NEDL1, translocon-associated protein-␦, and Dishevelled-1 forms a ubiquitinated protein complex that is included in potentially cytotoxic protein aggregates and that mutually affects their functions, leading to motor neuron death in FALS.Amyotrophic lateral sclerosis (ALS) 1 is a progressive, fatal, neurodegenerative disease that is characterized by selective loss of motor neurons in the spinal cord, brain stem, and motor cortex. The sporadic and familial forms of the disease have similar clinical and pathological features. About 10% of ALS cases are familial, and mutation of superoxide dismutase-1 (SOD1) is found in 20% of familial ALS (FALS) patients (1, 2). Mice that express mutant SOD1 transgenes develop an age-dependent ALS phenotype independent of levels of dismutase activity, suggesting that FALS pathology is because of a toxic gain of function in SOD1 and that the abnormal protein structure of mutant SOD1 is critical in the pathogenesis of motor neuron death (3-6). Recently, proteasome expression and activity have been reported to decrease with age in the spinal cord (7,8). Furthermore, mutant SOD1 turns over more rapidly than wild-type SOD1, and an inhibitor of proteasome action inhibits this turnover and thus selectively increases the steadystate level of mutant SOD1 (8). These results suggest the involvement of the ubiquitin-proteasome function in the cause of FALS. However, the biochemical nature of this gain-of-function mutation in SOD1 and the mechanism by which SOD1 mutations cause the degeneration of motor neurons have remained elusive.We show here the identification of a novel HECT-type ubiquitin-protein isopeptide ligase (E3), NEDL1, which is expressed in neuronal tissues, including the spinal cord, and selectively binds to and ubiquitinates mutant (but not wildtype) SOD1. NEDL1 is physically associated with transloconassociated protein-␦ (TRAP-␦), one of the endoplasmic reticulum (ER) translocon components that has previously been reported to bind mutant SOD...

To predict the prognosis of neuroblastoma patients and choose a better therapeutic protocol, we developed a cDNA microarray carrying 5340 genes obtained from primary neuroblastomas and examined 136 tumor samples. We made a probabilistic output statistical classifier that provided a high accuracy in prognosis prediction (89% at 5 years) and a highly reliable method to validate it. Kaplan-Meier analysis indicated that the patients in an intermediate group defined by existing markers are divided by microarray into two further groups with 5 year survivals for 36% and 89% of patients (p < 10(-4)), i.e., with unfavorably and favorably predicted neuroblastomas, respectively. According to these results, we developed a gene subset chip for a clinical tool, for which our classifier exhibited 88% prediction accuracy.

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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.

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