Gene-gene functional relationships in Alzheimer's disease: CELF1 regulates KLC1 alternative splicing.

The causes of Alzheimer's disease (AD) are poorly understood, although many genes are known to be involved in this pathology. To gain insights into the underlying molecular mechanisms, it is essential to identify the relationships between individual AD genes. Previous work has shown that the splice variant E of KLC1 (KLC1_vE) promotes AD, and that the CELF1 gene, which encodes an RNA-binding protein involved in splicing regulation, is at a risk locus for AD. Here, we identified a functional link between CELF1 and KLC1 in AD pathogenesis. Transcriptomic data from human samples from different ethnic groups revealed that CELF1 mRNA levels are low in AD brains, and the splicing pattern of KLC1 is strongly correlated with CELF1 expression levels. Specifically, KLC1_vE is negatively correlated with CELF1. Depletion and overexpression experiments in cultured cells demonstrated that the CELF1 protein down-regulates KLC1_vE. In a cross-linking and immunoprecipitation sequencing (CLIP-seq) database, CELF1 directly binds to KLC1 RNA, following which it likely modulates terminal exon usage, hence KLC1_vE formation. These findings reveal a new pathogenic pathway where a risk allele of CELF1 is associated with reduced CELF1 expression, which up-regulates KLC1_vE to promote AD.

PABPC1 mediates degradation of C9orf72-FTLD/ALS GGGGCC repeat RNA.

GGGGCC hexanucleotide repeat expansion in C9orf72 causes frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Expanded GGGGCC repeat RNA accumulates within RNA foci and is translated into toxic dipeptide repeat proteins; thus, efficient repeat RNA degradation may alleviate diseases. hnRNPA3, one of the repeat RNA-binding proteins, has been implicated in the destabilization of repeat RNA. Using APEX2-mediated proximity biotinylation, here, we demonstrate PABPC1, a cytoplasmic poly (A)-binding protein, interacts with hnRNPA3. Knockdown of PABPC1 increased the accumulation of repeat RNA and RNA foci to the same extent as the knockdown of hnRNPA3. Proximity ligation assays indicated PABPC1-hnRNPA3 and PABPC1-RNA exosomes, a complex that degrades repeat RNA, preferentially co-localized when repeat RNA was present. Our results suggest that PABPC1 functions as a mediator of polyadenylated GGGGCC repeat RNA degradation through interactions with hnRNPA3 and RNA exosome complex.

RNA Dysmetabolism and Repeat-Associated Non-AUG Translation in Frontotemporal Lobar Degeneration/Amyotrophic Lateral Sclerosis due to C9orf72 Hexanucleotide Repeat Expansion.

Neuropathological features of frontotemporal dementia and amyotrophic lateral sclerosis (ALS) due to C9orf72 GGGGCC hexanucleotide repeat expansion include early dipeptide repeats, repeat RNA foci, and subsequent TDP-43 pathologies. Since the discovery of the repeat expansion, extensive studies have elucidated the disease mechanism of how the repeat causes neurodegeneration. In this review, we summarize our current understanding of abnormal repeat RNA metabolism and repeat-associated non-AUG translation in C9orf72 frontotemporal lobar degeneration/ALS. For repeat RNA metabolism, we specifically focus on the role of hnRNPA3, the repeat RNA-binding protein, and the EXOSC10/RNA exosome complex, an intracellular RNA-degrading enzyme. In addition, the mechanism of repeat-associated non-AUG translation inhibition via TMPyP4, a repeat RNA-binding compound, is discussed.

Increased digital media use is associated with sleep problems among university students: A study during the COVID-19 pandemic in Japan.

This retrospective cohort study investigates the association between the incidence of sleep problems and changes in digital media use among university students during the COVID-19 pandemic. It used data from annual health check-ups performed at a Japanese university in 2019 and 2020. Students undergoing these check-ups were identified to respond to questions about sleep problems, digital media use, breakfast and exercise habits, and stress. In total, 3,869 students were included in the analysis. The association between the incidence of sleep problems in 2020 and the changes in digital media use between 2019 and 2020 was assessed using logistic regression models. The rate of long digital media use (≥ 2 hours) in 2019 was 42.6%, while in 2020 it was 53.6%. Incidence of sleep problems was observed in 244 students (6.3%) in 2020. There were 786 students (20.3%) who used digital media for ≤ 2 h in 2019 and ≥ 2 h in 2020. From the sample, 66 students (8.4%) reported incidence of sleep problems in 2020. Additionally, those respondents who specifically reported increased digital media use between 2019 and 2020 (increased use) where at greater risk (OR: 1.76; 95% CI: 1.21, 2.55) of reporting sleep problems in 2020, even after controlling for other study variables. Thus, this study provides evidence that the incidence of sleep problems has had a significant association with an increase in digital media use among university students throughout the COVID-19 pandemic. These findings highlight the importance of ensuring appropriate digital media use among students for improved quality of sleep.

Plasma NfL is associated with mild cognitive decline in patients with diabetes.

BACKGROUND: Patients with diabetes are at a higher risk for cognitive decline. Thus, biomarkers that can provide early and simple detection of cognitive decline are required. Neurofilament light chain (NfL) is a cytoskeletal protein that constitutes neural axons. Plasma NfL levels are elevated when neurodegeneration occurs. Here, we investigated whether plasma NfL levels were associated with cognitive decline in patients with type 2 diabetes. METHOD: This study included 183 patients with type 2 diabetes who visited Osaka University Hospital. All participants were tested for cognitive function using the Mini-Mental State Examination (MMSE) and the Rivermead Behavioural Memory Test (RBMT). NfL levels were analysed in the plasma and the relationship between NfL and cognitive function was examined. RESULTS: Lower RBMT-standardized profile scores (SPS) or MMSE scores correlated with higher plasma NfL levels (one-way analysis of variance: MMSE, P = 0.0237; RBMT-SPS, P = 0.0001). Furthermore, plasma NfL levels (ß = -0.34, P = 0.0005) and age (ß = -0.19, P = 0.016) were significantly associated with the RBMT score after multivariable regression adjustment. CONCLUSIONS: Plasma NfL levels were correlated with mild cognitive decline which is detected by the RBMT but not the MMSE in patients with type 2 diabetes. This suggests that plasma NfL levels may provide a valuable clinical tool for identifying mild cognitive decline in patients with diabetes.

Association of weekday-to-weekend sleep differences and stress response among a Japanese working population: a cross-sectional study.

OBJECTIVES: To investigate the relationship between differences in weekday-to-weekend sleep habits and stress responses in a working population. METHODS: This cross-sectional study used data from university workers on sleep habits, differences in sleep duration between weekdays and weekends, and each midpoint of the sleep phase on weekdays and weekends. Social jetlag was defined as the difference in the midpoint of the sleep phase between weekdays and weekends. In addition, the Brief Job Stress Questionnaire assessed stress responses and stress-related factors. To examine sleep-related factors affecting stress responses, regression analysis was performed with adjustments for age, sex, and stress-related factors. RESULTS: Analyzed were 2,739 participants. Sleep duration differences obtained by subtracting sleep duration on weekdays from that on weekends, social jetlag, and weekday sleep duration were significantly associated with an increased risk of stress responses in a univariate linear regression model. Adjusting for age, sex, job stressors, and stressor buffering factors did not change this trend. However, when additionally adjusting for all sleep parameters, only sleep duration differences and weekday sleep duration were significantly associated with stress responses (ß 0.67 [95% CI 0.24, 1.10], p = 0.002), (-0.66 [-1.20, -0.13], p = 0.015). CONCLUSIONS: This study provided further evidence that weekday sleep duration and weekday-to-weekend sleep duration differences were independently associated with stress responses even when considering stress-related factors. However, social jetlag was not clearly associated with stress responses. Our findings highlighted the necessity of securing sufficient sleep for stress management and mental health promotion in a working population.

Renal function is associated with blood neurofilament light chain level in older adults.

Neurofilament light chain (NfL) is a novel biomarker of neurodegenerative diseases. It is detectable in the peripheral blood, allowing low-invasive assessment of early signs of neurodegeneration. The level of NfL gradually increases with age; however, what other factors affect it remains unclear. The present study examined the association between blood NfL level and renal function among healthy participants undergoing a health check (n = 43, serum NfL) and patients with diabetes mellitus (n = 188, plasma NfL). All participants were 60 years of age or older; none were diagnosed with dementia. In each group, levels of blood NfL and serum creatinine significantly correlated (coefficient r = 0.50, 0.56). These associations remained statistically significant even after adjustment for age, sex, and body mass index. These findings indicate that blood NfL level might be partially affected by renal function. We recommend measuring renal function for a more precise evaluation of neuroaxonal damage, in particular, among older adults.