Exome sequencing identifies novel genes associated with cerebellar volume and microstructure.

Proteins encoded by exons are critical for cellular functions, and mutations in these genes often result in significant phenotypic effects. The cerebellum is linked to various heritable human disease phenotypes, yet genome-wide association studies have struggled to capture the effects of rare variants on cerebellar traits. This study conducts a large-scale exome association analysis using data from approximately 35,000 UK Biobank participants, examining seven cerebellar traits, including total cerebellar volume and white matter microstructure.

Differential roles of IL-17B and IL-17RB in colorectal cancer: Correlation with immune infiltration and prognosis.

Background: The aim of the research is to investigate correlation of immune infiltration between IL-17B and IL-17RB in colorectal cancer (CRC), then provide an experimental basis for clinical diagnostic marker screening of CRC.

Methods: Gene expression levels were assessed via TIMER and GEPIA databases, protein expression through the Human Protein Atlas (HPA), clinicopathological correlations and prognosis via UALCAN and KM-Plotter, respectively. Mutation analysis was conducted using cBioPortal, immune cell infiltration via TIMER, and hub genes were identified through protein-protein interaction (PPI) networks.

The neuroprotective effects of cholecystokinin in the brain: antioxidant, anti-inflammatory, cognition, and synaptic plasticity.

Cholecystokinin (CCK) is a major neuropeptide in the brain that functions as a neurotransmitter, hormone, and growth factor. The peptide and its receptors are widely expressed in the brain. CCK signaling modulates synaptic plasticity and can improve or impair memory formation, depending on the brain areas studies and the receptor subtype activated.

E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.

The carboxyl terminus of Hsc70-interacting protein (CHIP) is pivotal for managing misfolded and aggregated proteins via chaperone networks and degradation pathways. In a preclinical rodent model of CHIP-related ataxia, we observed that CHIP mutations lead to increased levels of phosphodiesterase 9A (PDE9A), whose role in this context remains poorly understood. Here, we investigated the molecular mechanisms underlying the role of PDE9A in CHIP-related ataxia and demonstrated that CHIP binds to PDE9A, facilitating its polyubiquitination and autophagic degradation.

Annexin A1: The dawn of ischemic stroke (Review).

Ischemic stroke is a prevalent clinical condition that poses a significant global challenge. Developing innovative strategies to address this issue is crucial. Annexin A1 (ANXA1), a key member of the annexin superfamily, performs various functions, such as inhibiting inflammatory factor release, promoting phagocytosis, and blocking leukocyte migration.

Microvascular and cellular dysfunctions in Alzheimer's disease: an integrative analysis perspective.

Alzheimer's disease (AD) is the most common cause of dementia, characterized by memory loss, cognitive decline, personality changes, and various neurological symptoms. The role of blood-brain barrier (BBB) injury, extracellular matrix (ECM) abnormalities, and oligodendrocytes (ODCs) dysfunction in AD has gained increasing attention, yet the detailed pathogenesis remains elusive. This study integrates single-cell sequencing of AD patients' cerebrovascular system with a genome-wide association analysis.

Expression and immune infiltration studies of IL-33-ST2-NF-κB signaling pathway in prostate cancer.

Background: To analyze the expression of interleukin-33 (IL-33), growth-stimulated expression gene 2 (ST2), nuclear factor-kappaB (NF-κB) and immune cell infiltration in prostate cancer, this study aims to provide an experimental basis for the clinical prevention and treatment of prostate cancer.

Methods: The expression of IL-33 in PCa tissues was analyzed using TCGA, TIMER and HPA databases. Using the UALCAN database, the systematic exploration of the relationship between IL-33 and various clinicopathological parameters was conducted.

The potential protective role of peripheral immunophenotypes in Alzheimer's disease: a Mendelian randomization study.

Introduction: Alzheimer's disease (AD) is the most widespread neurodegenerative disease in the world. Previous studies have shown that peripheral immune dysregulation plays a paramount role in AD, but whether there is a protective causal relationship between peripheral immunophenotypes and AD risk remains ambiguous.

Methods: Two-sample Mendelian randomization (MR) was performed using large genome-wide association study (GWAS) genetic data to assess causal effects between peripheral immunophenotypes and AD risk.

Peripheral immune cell traits and Parkinson's disease: A Mendelian randomization study.

Background: The peripheral immune system is altered in Parkinson's disease (PD), but the causal relationship between the two remains controversial. In this study, we aimed to estimate the causal relationship between peripheral immune features and PD using a two-sample Mendelian randomization (MR) approach.

Methods: Genome-wide association study (GWAS) data of peripheral blood immune signatures from European populations were used for exposure and PD summary statistics were used as results.

Association between inflammatory bowel disease and Parkinson's disease: a prospective cohort study of 468,556 UK biobank participants.

Introduction: Inflammatory Bowel Disease (IBD) and Parkinson's disease (PD) are both chronic, progressive disorders. As such, given the inconclusive results of extensive research on the association between IBD and PD, our study intends to examine this relationship further using the UK Biobank database.

Methods: We conducted a prospective cohort study using the Cox proportional hazards model, analyzing data from the UK Biobank to investigate the relationship between IBD and PD, following subjects until PD diagnosis, loss to follow up, death or study termination on 30 June, 2023.

Joint analysis of proteome, transcriptome, and multi-trait analysis to identify novel Parkinson's disease risk genes.

Genome-wide association studies (GWAS) have identified multiple risk variants for Parkinson's disease (PD). Nevertheless, how the risk variants confer the risk of PD remains largely unknown. We conducted a proteome-wide association study (PWAS) and summary-data-based mendelian randomization (SMR) analysis by integrating PD GWAS with proteome and protein quantitative trait loci (pQTL) data from human brain, plasma and CSF.

A large pedigree study confirmed the CGG repeat expansion of RILPL1 Is associated with oculopharyngodistal myopathy.

Background: Oculopharyngodistal myopathy (OPDM) is an autosomal dominant adult-onset degenerative muscle disorder characterized by ptosis, ophthalmoplegia and weakness of the facial, pharyngeal and limb muscles. Trinucleotide repeat expansions in non-coding regions of LRP12, G1PC1, NOTCH2NLC and RILPL1 were reported to be the etiologies for OPDM.

Results: In this study, we performed long-read whole-genome sequencing in a large five-generation family of 156 individuals, including 21 patients diagnosed with typical OPDM.

Identifying causal genes for migraine by integrating the proteome and transcriptome.

Background: While previous genome-wide association studies (GWAS) have identified multiple risk variants for migraine, there is a lack of evidence about how these variants contribute to the development of migraine. We employed an integrative pipeline to efficiently transform genetic associations to identify causal genes for migraine.

Methods: We conducted a proteome-wide association study (PWAS) by combining data from the migraine GWAS data with proteomic data from the human brain and plasma to identify proteins that may play a role in the risk of developing migraine.

GGC repeat expansion in NOTCH2NLC induces dysfunction in ribosome biogenesis and translation.

GGC repeat expansion in the 5' untranslated region (UTR) of NOTCH2NLC is associated with a broad spectrum of neurological disorders, especially neuronal intranuclear inclusion disease (NIID). Studies have found that GGC repeat expansion in NOTCH2NLC induces the formation of polyglycine (polyG)-containing protein, which is involved in the formation of neuronal intranuclear inclusions. However, the mechanism of neurotoxicity induced by NOTCH2NLC GGC repeats is unclear.

Hederagenin improves Alzheimer's disease through PPARα/TFEB-mediated autophagy.

Background: Autophagic flux is coordinated by a network of master regulatory genes, which centered on transcription factor EB (TFEB). The disorders of autophagic flux are closely associated with Alzheimer's disease (AD), and thus restoring autophagic flux to degrade pathogenic proteins has become a hot therapeutic strategy. Hederagenin (HD), a triterpene compound, isolated from a variety food such as Matoa (Pometia pinnata) Fruit, Medicago sativa, Medicago polymorpha L.

Intelligence, education level, and risk of Parkinson's disease in European populations: A Mendelian randomization study.

A high level of education or intelligence (IQ) is reported to be a risk factor for Parkinson's disease (PD). The purpose of this study was to systematically examine the causal relationships between IQ, educational attainment (EA), cognitive performance, and PD. We used summary statistics from genome-wide association studies on IQ, EA, cognitive performance, and PD.

Human blood metabolites and lacunar stroke: A Mendelian randomization study.

Background: Lacunar stroke accounts for a quarter of all strokes, but little is known about the underlying pathological mechanisms. Analysis of serum metabolites may allow better understanding of the underlying biological processes. Mendelian randomization (MR) can provide information on the causality of associations.

The APP intracellular domain promotes expression to enable feed-forward neurodegenerative mechanisms in Parkinson's disease.

Gain-of-function mutations in the leucine-rich repeat kinase 2 () gene are common in familial forms of Parkinson's disease (PD), which is characterized by progressive neurodegeneration that impairs motor and cognitive function. We previously demonstrated that LRRK2-mediated phosphorylation of β-amyloid precursor protein (APP) triggers the production and nuclear translocation of the APP intracellular domain (AICD). Here, we connected LRRK2 to AICD in a feed-forward cycle that enhanced LRRK2-mediated neurotoxicity.