A5067326228- Neurogenetic and Muscular Disorders Research
- Genetic Neurodegenerative Diseases
- RNA Research and Splicing
- Muscle Physiology and Disorders
- RNA modifications and cancer
- Inflammatory Myopathies and Dermatomyositis
- Neurological diseases and metabolism
- Mitochondrial Function and Pathology
- Congenital Anomalies and Fetal Surgery
- Cardiac Structural Anomalies and Repair
- Alzheimer's disease research and treatments
- Amyotrophic Lateral Sclerosis Research
- Parkinson's Disease Mechanisms and Treatments
- Neurological disorders and treatments
- RNA and protein synthesis mechanisms
- Glycogen Storage Diseases and Myoclonus
- Cancer-related molecular mechanisms research
- Parkinson's Disease and Spinal Disorders
- Platelet Disorders and Treatments
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Neurological and metabolic disorders
- Biotin and Related Studies
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Ophthalmology and Eye Disorders
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Nagoya University
2016-2025
Tokai National Higher Education and Research System
2024
Nagoya City University
2019
Cold Spring Harbor Laboratory
2010-2018
Kobe University
2007
Mayo Clinic
1979
Increasing survival of motor neuron 2, centromeric (SMN2) exon 7 inclusion to express more full-length SMN protein in neurons is a promising approach treat spinal muscular atrophy (SMA), genetic neurodegenerative disease. Previously, we identified potent 2'-O-(2-methoxyethyl) (MOE) phosphorothioate-modified antisense oligonucleotide (ASO) that blocks an SMN2 intronic splicing silencer element and efficiently promotes transgenic mouse peripheral tissues after systemic administration. Here...
X-linked spinal and bulbar muscular atrophy (SBMA), a motor neuron disease associated with androgen insensitivity, is caused by receptor gene mutations an increased number of tandem CAG repeats in exon 1. We investigated the genes 19 SBMA patients found that this correlated strongly age at onset muscle weakness. Thus, first genetic which strong correlation between degree abnormality (number repeats) clinical phenotypic expression demonstrable. The results further indicate mutation directly...
Survival of motor neuron (SMN) deficiency causes spinal muscular atrophy (SMA), but the pathogenesis mechanisms remain elusive. Restoring SMN in neurons only partially rescues SMA mouse models, although it is thought to be therapeutically essential. Here, we address relative importance restoration central nervous system (CNS) versus peripheral tissues models using a therapeutic splice-switching antisense oligonucleotide restore and complementary decoy neutralize its effects CNS. Increasing...
Familial dysautonomia (FD) is a rare inherited neurodegenerative disorder caused by point mutation in the IKBKAP gene that results defective splicing of its pre-mRNA. The weakens 5′ splice site exon 20, causing this to be skipped, thereby introducing premature termination codon. Though detailed FD pathogenesis mechanisms are not yet clear, correcting defect relevant tissue(s), thus restoring normal expression levels full-length IKAP protein, could therapeutic. Splice-switching antisense...
Spinal and bulbar muscular atrophy (SBMA), an adult-onset neurodegenerative disease that affects males, results from a CAG triplet repeat/polyglutamine expansions in the androgen receptor (AR) gene. Patients develop progressive weakness atrophy, no effective therapy is currently available. The tissue-specific pathogenesis, especially relative pathological contributions between degenerative motor neurons muscles, remains inconclusive. Though peripheral pathology skeletal muscle caused by...
We have found that two previously reported exonic mutations in the PINK1 and PARK7 genes affect pre-mRNA splicing. To develop an algorithm to predict underestimated splicing consequences of at 5′ splice site, we constructed analyzed 31 minigenes carrying their derivatives. also examined 189 249 U2-dependent sites entire human genome a new variable, SD-Score, which represents common logarithm frequency specific efficiently predicts these minigenes. employed information contents (R i ) improve...
Loss-of-function mutations in SMN1 cause spinal muscular atrophy (SMA), a leading genetic of infant mortality. The related SMN2 gene expresses suboptimal levels functional SMN protein, due to splicing defect. Many SMA patients reach adulthood, and there is also adult-onset (type IV) SMA. There currently no animal model for SMA, the tissue-specific pathogenesis post-developmental deficiency remains elusive. Here, we use an antisense oligonucleotide (ASO) exacerbate mis-splicing....
While amyloid-β lies upstream of tau pathology in Alzheimer’s disease, key drivers for other tauopathies, including progressive supranuclear palsy (PSP), are largely unknown. Various mutations known to facilitate aggregation, but how the nonmutated tau, which most cases with PSP share, increases its propensity aggregate neurons and glial cells has remained elusive. Here, we identified genetic variations protein abundance filamin-A brains without mutations. We provided vivo biochemical...
Antisense oligonucleotides (ASOs) are versatile molecules that can be designed to specifically alter splicing patterns of target pre-mRNAs. Here we exploit this feature phenocopy a genetic disease. Spinal muscular atrophy (SMA) is motor neuron disease caused by loss-of-function mutations in the SMN1 gene. The related SMN2 gene expresses suboptimal levels functional SMN protein due alternative skips exon 7; correcting defect-e.g., with ASOs-is promising therapeutic approach. We describe use...
Polyglutamine (polyQ) diseases are inherited neurodegenerative disorders caused by expansion of cytosine-adenine-guanine (CAG)-trinucleotide repeats in causative genes. These include spinal and bulbar muscular atrophy (SBMA), Huntington's disease, dentatorubral-pallidoluysian atrophy, spinocerebellar ataxias. Targeting expanded CAG is a common therapeutic approach to polyQ diseases, but concomitant silencing genes with normal may lead toxicity. Previous studies have shown that...
The abnormal aggregation of TDP-43 into cytoplasmic inclusions in affected neurons is a pathological hallmark amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although how forms aggregates causes neurodegeneration patients with ALS/FTD remains unclear, reducing cellular levels likely to prevent rescue from toxicity. To address this issue, here we developed gapmer-type antisense oligonucleotides (ASOs) against human using 2'-O,4'-C-ethylene nucleic acids (ENAs), which...
Tau, a microtubule-binding protein linked to tauopathies like Alzheimer's disease and frontotemporal lobar degeneration (FTLD), has 3-repeat (3R) 4-repeat (4R) isoforms. Accumulation of the 4R-tau is associated with FTLD, progressive supranuclear palsy (PSP), cortico-basal (CBD). We previously showed that loss fused in sarcoma (FUS) or splicing factor, proline- glutamine-rich (SFPQ) promoted accumulation, which induced FTLD-like behaviors neurodegeneration mice. Here, we developed antisense...
Herein, we present a case of severe immune-related adverse events (irAEs), myocarditis with myositis, and myasthenia gravis overlap syndrome (IM3OS) in patient receiving an immune checkpoint inhibitor (ICI), as adjuvant therapy after surgery for muscle-invasive bladder cancer. An 80-year-old woman who had undergone total cystectomy cancer presented ptosis, diplopia, paralysis 18 days nivolumab, anti-programmed cell death-1 (PD-1) monoclonal antibody, the first time. Initial testing revealed...
Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine-mediated neuromuscular disease caused by CAG repeat expansion in the androgen receptor (AR) gene. While transcriptional dysregulation known to play critical role pathogenesis of SBMA, underlying molecular pathomechanisms remain unclear. DNA methylation fundamental epigenetic modification that silences transcription various genes have CpG-rich promoter. Here, we showed methyltransferase 1 (Dnmt1) highly expressed spinal motor...
Spinal muscular atrophy (SMA) is an intractable neuromuscular disorder primarily caused by homozygous deletions in exon 7 of the SMN1 gene. Early diagnosis and prompt treatment patients with SMA have a significant impact on prognosis, several therapies recently been developed. Current screening tests require turnaround time to identify suspected SMA, due both interval between birth newborn collection blood for mass difficulty distinguishing SMN2 , paralog gene that requires testing...
Immune-mediated myopathies with antibodies may be triggered by statin exposure, but some patients these disorders are statin-naive; thus, there probably other etiologies.1 Several malignant tumors, including esophageal squamous cell carcinoma (ESCC), overexpress 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) protein.2 To date, the relationship between anti-HMGCR antibody–associated myopathy (HMGCR-M) and malignancy remains unclear.3,4 Here, we report a case of HMGCR-M in patient ESCC...
Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by an expanded CAG repeat in the androgen receptor (AR) gene. Here, we perform comprehensive analysis of signaling pathways mouse model SBMA (AR-97Q mice) utilizing phosphoprotein assay. We measure levels 17 phosphorylated proteins spinal cord skeletal muscle AR-97Q mice at three stages. The level Src (p-Src) markedly increased cords muscles prior to onset. Intraperitoneal administration kinase inhibitor improves...
Abstract Background Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by the expansion of trinucleotide cytosine–adenine–guanine (CAG) repeats, which encodes polyglutamine (polyQ) tract in androgen receptor ( AR ) gene. Recent evidence suggests that, addition to motor neuron degeneration, defective skeletal muscles are also primary contributors pathogenesis SBMA. While benefits physical exercise have been suggested SBMA, underlying mechanism remains...