A5063835821- Genetic Neurodegenerative Diseases
- Mitochondrial Function and Pathology
- RNA Research and Splicing
- DNA Repair Mechanisms
- Alzheimer's disease research and treatments
- Ubiquitin and proteasome pathways
- Genetics and Neurodevelopmental Disorders
- Amyotrophic Lateral Sclerosis Research
- Neurogenesis and neuroplasticity mechanisms
- Muscle Physiology and Disorders
- Genetics, Aging, and Longevity in Model Organisms
- Nerve injury and regeneration
- RNA modifications and cancer
- Metabolism and Genetic Disorders
- Hippo pathway signaling and YAP/TAZ
- Neuroinflammation and Neurodegeneration Mechanisms
- RNA and protein synthesis mechanisms
- Autophagy in Disease and Therapy
- Neuroscience and Neuropharmacology Research
- Cholinesterase and Neurodegenerative Diseases
- RNA regulation and disease
- Signaling Pathways in Disease
- Hereditary Neurological Disorders
- Parkinson's Disease Mechanisms and Treatments
- Neurobiology and Insect Physiology Research
Tokyo Medical and Dental University
2015-2024
Tokyo Institute of Psychiatry
2024
Institute of Science Tokyo
2024
The University of Tokyo
1993-2020
Japan Science and Technology Agency
2003-2013
Toho University
2012
Tokyo Medical University
2011
Tokyo Metropolitan Institute of Medical Science
2003-2008
Fuchu Hospital
2002-2006
Laboratoire de Microbiologie et Génétique Moléculaires
1998
Brain inflammation generally accompanies and accelerates neurodegeneration. Here we report a microglial mechanism in which polyglutamine binding protein 1 (PQBP1) senses extrinsic tau 3R/4R proteins by direct interaction triggers an innate immune response activating cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) pathway. Tamoxifen-inducible microglia-specific depletion PQBP1 primary culture vitro mouse brain vivo shows that is essential for sensing-tau to induce...
Cystathionine beta-synthase (CBS; EC 4.2.1.22) is a key enzyme in the generation of cysteine from methionine. A deficiency CBS leads to homocystinuria, an inherited human disease characterized by mental retardation, seizures, psychiatric disturbances, skeletal abnormalities, and vascular disorders; however, underlying mechanisms remain largely unknown. Here, we show regional cellular distribution adult developing mouse brain. In brain, was expressed ubiquitously, but it most intensely...
Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disease, but it remains an intractable condition. Its pathogenesis predominantly attributed to aggregation and transmission of two molecules, Aβ tau; however, other pathological mechanisms are possible. Here, we reveal that phosphorylation MARCKS, a submembrane protein regulates stability actin network, occurs at Ser46 prior sustained throughout course AD in human mouse brains. Furthermore, HMGB1 released from necrotic or...
A promising therapeutic approach for Duchenne muscular dystrophy (DMD) is exon skipping using antisense oligonucleotides (AOs). In-frame deletions of the hinge 3 region dystrophin protein, which encoded by exons 50 and 51, are predicted to cause a variety phenotypes. Here, we performed functional analyses muscle in 52-deleted mdx (mdx52) mouse, predict function in-frame following 51-skipping, leads protein lacking most 3. series AOs based on phosphorodiamidate morpholino oligomers was...
DNA repair defends against naturally occurring or disease-associated damage during the long lifespan of neurons and is implicated in polyglutamine disease pathology. In this study, we report that mutant huntingtin (Htt) expression causes double-strand breaks (DSBs) genomic DNA, Htt further promotes DSBs by impairing repair. We identify Ku70, a component complex, as mediator dysfunction Htt–expressing neurons. Mutant interacts with impairs DNA-dependent protein kinase function nonhomologous...
Abstract The timing and characteristics of neuronal death in Alzheimer’s disease (AD) remain largely unknown. Here we examine AD mouse models with an original marker, myristoylated alanine-rich C-kinase substrate phosphorylated at serine 46 (pSer46-MARCKS), reveal increase necrosis during pre-symptomatic phase a subsequent decrease symptomatic phase. Postmortem brains mild cognitive impairment (MCI) rather than patients remarkable necrosis. In vivo imaging reveals instability endoplasmic...
Polyglutamine binding protein 5 (PQBP5), also called nucleolar 10 (NOL10), binds to polyglutamine tract sequences and is expressed in the nucleolus. Using dynamic imaging of high-speed atomic force microscopy, we show that PQBP5/NOL10 an intrinsically disordered protein. Super-resolution microscopy correlative light electron method makes up skeletal structure nucleolus, constituting granule meshwork granular component area, which distinct from other substructures, such as fibrillar center...
A novel gene, designated PQBP-1, which encodes a 265 residue protein that binds to the polyglutamine tract of brain-specific transcription factor Brn-2, was identified. also interacts with triplet repeat disease gene products, higher affinity an expanded tract. PQBP-1 has several functional domains, including hepta- and di-amino acid sequences rich in polar residues essential for its interaction tract, WWP/WW domain proline-rich motifs other proteins, putative nuclear localization signal...
We investigated the effect of dopamine on in vivo expression brain‐derived neurotrophic factor (BDNF) striatum mouse. BDNF mRNA striation, which was Quantified with reverse transcriptase polymerase chain reaction, up‐repulated from 2 h after oral administration levodopa, a precursor dopamine. The increase sustained for 16 h. Co‐administrstion haloperidol partially inhibited dopamine‐induced enhancement. These data suggest that dopaminergic stimulation directly promotes vivo.
Abstract Mutant ataxin‐1 (Atxn1), which causes spinocerebellar ataxia type 1 ( SCA 1), binds to and impairs the function of high‐mobility group box HMGB a crucial nuclear protein that regulates DNA architectural changes essential for damage repair transcription. In this study, we established transgenic or virus vector‐mediated complementation with ameliorates motor dysfunction prolongs lifespan in mutant Atxn1 knock‐in (Atxn1‐ KI ) mice. We identified mitochondrial by as novel molecular...
Using a high-end mass spectrometry, we screened phosphoproteins and phosphopeptides in four types of Alzheimer's disease (AD) mouse models human AD postmortem brains. We identified commonly changed multiple also determined related to initiation amyloid beta (Aβ) deposition the brain. After confirming these proteins were brains, put on experimentally verified protein–protein interaction databases. Surprisingly, most core directly connected, they formed functional network linked synaptic spine...
Abstract We developed a new technique to observe macroautophagy in the brain vivo and examined whether fasting induced neurons how induction was different between Alzheimer’s disease (AD) model control mice. Lentivirus for EGFP-LC3 injected into successfully visualized autophagosome living by two-photon microscopy. The time-lapse imaging revealed that increased number, size signal intensity of neurons. In AD mice, these parameters were higher at basal levels before starvation more rapidly...
Neurite orientation dispersion and density imaging (NODDI) is a diffusion magnetic resonance (MRI) technique with the potential to visualize microstructure of brain. Revolutionary histological methods render mouse brain transparent have recently been developed, but verification NODDI by these has not reported.To confirm concordance histology in terms neurites brain.Whole MRI thy-1 yellow fluorescent protein was acquired 7-T scanner, after which sections were created from same mouse....
The mechanisms of neuronal cell death in neurodegenerative disease remain incompletely understood, although recent studies have made significant advances. Apoptosis was previously considered to be the only mechanism diseases. However, findings challenged this dogma, identifying new subtypes necrotic death. present review provides an updated summary necrosis and discusses their potential roles Among numerous subtypes, including necroptosis, paraptosis, ferroptosis, pyroptosis, transcriptional...
Aggregation of huntingtin (htt) in neuronal inclusions is associated with the development Huntington's disease (HD). Previously, we have shown that mutant htt fragments polyglutamine (polyQ) tracts pathological range (>37 glutamines) form SDS-resistant aggregates a fibrillar morphology, whereas wild-type normal polyQ domains do not aggregate. In this study investigated co-aggregation and fragments. We found promotes aggregation htt, causing formation co-aggregates morphology. Conversely,...
We report here that all trans-retinoic acid (RA), a classical morphogen, induces apoptosis during the neural differentiation of embryonic stem cell line P19. The apoptotic cells showed, in addition to DNA cleavage, typical morphological changes including chromatin condensation, nuclear fragmentation, and cytoplasmic vacuolation. These became obvious by 12 h after RA. endogenous expression bcl-2 surviving was down-regulated this process, compelled retroviral vectors reduced number cells....
ABSTRACT Previous studies using transfected cells have indicated that the mammalian receptor tyrosine kinase trkB binds neurotrophins brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4. However, most demonstrating these prevent death of embryonic neurons specific neuronal receptors been performed with chick neurons. In order to explore possibility is molecular entity representing high-affinity for factor on neurons, we cloned expressed a cDNA. situ hybridisation results...
Transcriptional disturbance is implicated in the pathology of polyglutamine diseases, including Huntington's disease (HD). However, it unknown whether transcriptional repression leads to neuronal death or what forms that might take. We found repression-induced atypical (TRIAD) neurons be distinct from apoptosis, necrosis, autophagy. The progression TRIAD was extremely slow comparison with other types cell death. Gene expression profiling revealed reduction full-length yes-associated protein...