A5013228667- Amyotrophic Lateral Sclerosis Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Neurogenetic and Muscular Disorders Research
- Neurogenesis and neuroplasticity mechanisms
- Alzheimer's disease research and treatments
- Cholinesterase and Neurodegenerative Diseases
- Parkinson's Disease Mechanisms and Treatments
- Tryptophan and brain disorders
- Immune cells in cancer
- RNA Research and Splicing
- Neuroblastoma Research and Treatments
- Neuroscience and Neuropharmacology Research
- Nuclear Receptors and Signaling
- Pharmacological Receptor Mechanisms and Effects
- Prion Diseases and Protein Misfolding
- Neurological diseases and metabolism
- Glycosylation and Glycoproteins Research
- ATP Synthase and ATPases Research
- Developmental Biology and Gene Regulation
- Animal Vocal Communication and Behavior
- interferon and immune responses
- Regulation of Appetite and Obesity
- Nicotinic Acetylcholine Receptors Study
- Neurological Disease Mechanisms and Treatments
- Endoplasmic Reticulum Stress and Disease
Nagoya University
2015-2025
RIKEN Center for Brain Science
2014
Tokyo Medical and Dental University
2005-2013
University of Pennsylvania
2011
A homozygous mutation in the gene for sigma 1 receptor (Sig1R) is a cause of inherited juvenile amyotrophic lateral sclerosis (ALS16). Sig1R localizes to mitochondria-associated membrane (MAM), which an interface mitochondria and endoplasmic reticulum. However, role MAM ALS not fully elucidated. Here, we identified p.L95fs as novel ALS16. ALS-linked variants were unstable incapable binding inositol 1,4,5-triphosphate type 3 (IP3R3). The onset mutant Cu/Zn superoxide dismutase (SOD1)-mediated...
Abstract Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer’s disease (AD). Although microglia aging and neurodegenerative model mice show a loss homeostatic phenotype activation disease-associated (DAM), correlation between those phenotypes degree neuronal cell not clarified. In this study, we performed RNA sequencing isolated from three representative mouse models, App NL - G F/NL F with amyloid pathology, rTg4510 tauopathy, SOD1 G93A motor neuron by...
Neuroinflammation, which includes both neuroprotective and neurotoxic reactions by activated glial cells infiltrated immune cells, is involved in the pathomechanism of amyotrophic lateral sclerosis (ALS). However, cytokines that regulate inflammatory response ALS are not clear. Here, we identify transforming growth factor-β1 (TGF-β1), upregulated astrocytes murine human ALS, as a negative regulator response. We demonstrate astrocyte-specific overproduction TGF-β1 SOD1G93A mice accelerates...
Cellular senescence, a state of irreversible cell-cycle arrest caused by variety cellular stresses, is critically involved in age-related tissue dysfunction various organs. However, the features cells central nervous system that undergo senescence and their role neural impairment are not well understood as yet. Here, through comprehensive investigations utilising single-cell transcriptome analysis mouse models, we show microglia, particularly white matter, brain spinal cord during ageing...
Histological chorioamnionitis (HCA) is a form of maternal immune activation (MIA) linked to an increased risk neurodevelopmental disorders in offspring. Our previous study identified impairments MIA mouse model mimicking HCA. Thus, this investigated the role CD11c+ microglia, key contributors myelination through IGF-1 production, pathology. In model, microglial population was significantly lower group than control on postnatal day 3 (PN3d). Furthermore, myelination-related protein levels...
Article22 September 2020Open Access Source DataTransparent process Astrocytic phagocytosis is a compensatory mechanism for microglial dysfunction Hiroyuki Konishi Corresponding Author [email protected] orcid.org/0000-0002-4321-8339 Department of Functional Anatomy and Neuroscience, Nagoya University Graduate School Medicine, Nagoya, Japan Search more papers by this author Takayuki Okamoto Yuichiro Hara Genetics, Research Institute Environmental University, Human Genetics Molecular Biology,...
Abstract Neuroinflammation, which is characterized by activated microglia, astrocytes, infiltrating immune cells and the subsequent production of inflammatory mediators, linked to a pathological process common neurodegenerative diseases, such as Alzheimer's disease amyotrophic lateral sclerosis ( ALS ). Furthermore, increasing evidence suggests that glial surrounding motor neurons also contribute non‐cell autonomous neurodegeneration through neuroinflammation mediated these non‐neuronal...
The cytoplasmic aggregation of TAR DNA binding protein-43 (TDP-43), also known as TDP-43 pathology, is the pathological hallmark amyotrophic lateral sclerosis (ALS). However, mechanism underlying mislocalization and subsequent remains unclear. Here, we show that dimerization/multimerization impaired in postmortem brains spinal cords patients with sporadic ALS N-terminal dimerization–deficient consists inclusion bodies motor neurons. Expression mutant Neuro2a cells induced pluripotent stem...
Dominant mutations in superoxide dismutase 1 (SOD1) cause degeneration of motor neurons a subset inherited amyotrophic lateral sclerosis (ALS). The pathogenetic process mediated by misfolded and/or aggregated mutant SOD1 polypeptides is hypothesized to be suppressed protein refolding. This genetic study aimed test whether SOD1-mediated ALS pathology recapitulated mice could alleviated overexpressing longevity-related deacetylase SIRT1 whose substrates include transcription factor heat shock...
Abstract Background Neuroinflammation substantially contributes to the pathology of Alzheimer’s disease (AD), most common form dementia. Studies have reported that nuclear factor erythroid 2-related 2 (Nrf2) attenuates neuroinflammation in mouse models neurodegenerative diseases, however, detailed mechanism remains unclear. Methods The effects dimethyl fumarate (DMF), a clinically used drug activate Nrf2 pathway, on were analyzed primary astrocytes and App NL−G−F ( -KI) mice. cognitive...
Recent single-cell analyses have revealed the complexity of microglial heterogeneity in brain development, aging, and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Disease-associated microglia (DAMs) been identified ALS mice model, but their role pathology remains unclear. The effect genetic background variations on functions unknown. Herein, we established analyzed two models with distinct backgrounds C57BL/6 BALB/c. We observed that change from to BALB/c affected...
Increasing evidence implicates the role of cell types surrounding motor neurons, such as interneurons and glial cells, in non-cell autonomous neurodegeneration amyotrophic lateral sclerosis (ALS). C-boutons, large cholinergic synapses that innervate spinal α-motor neurons to control their excitability, are progressively lost from both human ALS mutant Cu/Zn superoxide dismutase 1 (SOD1)-ALS mice. Neuregulin-1 (NRG1), a trophic factor implicated neural development, transmission, synaptic...
Abstract Cytoplasmic inclusion of TAR DNA-binding protein 43 (TDP-43) is a pathological hallmark amyotrophic lateral sclerosis (ALS) and subtype frontotemporal lobar degeneration (FTLD). Recent studies have suggested that the formation cytoplasmic TDP-43 aggregates dependent on liquid–liquid phase separation (LLPS) mechanism. However, it unclear whether pathology induced through single intracellular mechanism such as LLPS. To identify mechanisms responsible for aggregation, we established...
There is compelling evidence that glial-immune interactions contribute to the progression of neurodegenerative diseases. The adaptive immune response has been implicated in disease processes amyotrophic lateral sclerosis (ALS), but it remains unknown if innate signaling also contributes ALS progression. Here we report deficiency adaptor TIR domain-containing inducing interferon-β (TRIF), which essential for certain Toll-like receptor (TLR) cascades, significantly shortens survival time and...
Abstract Abnormal accumulation of TAR DNA-binding protein 43 (TDP-43), a DNA/RNA binding protein, is pathological signature amyotrophic lateral sclerosis (ALS). Missense mutations in the TARDBP gene are also found inherited and sporadic ALS, indicating that dysfunction TDP-43 causative for ALS. To model TDP-43-linked ALS rodents, we generated knock-in mice with patient-derived M337V mutation. Homozygous developed normally without exhibiting detectable motor neurodegeneration. However,...
Organelle contact sites are multifunctional platforms for maintaining cellular homeostasis. Alternations of the mitochondria-associated membranes (MAM), one organelle where endoplasmic reticulum (ER) is tethered to mitochondria, have been involved in pathogenesis neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, detailed mechanisms through which MAM integrity disrupted ALS not fully elucidated. Here, we examined whether AAA ATPase domain-containing protein...
Glutamate transporters are essential for terminating excitatory neurotransmission. Two distinct glutamate transporters, glutamate–aspartate transporter (GLAST) and amino acid 4 (EAAT4), expressed most abundantly in the molecular layer of cerebellar cortex. GLAST is Bergmann glial processes surrounding synapses on Purkinje cell dendritic spines, whereas EAAT4 concentrated extrasynaptic regions spine membranes. To clarify functional significance coexistence these we analyzed kinetics EPSCs...
The mitochondria-associated membrane (MAM) is a functional subdomain of the endoplasmic reticulum that tethers to mitochondrial outer and essential for cellular homeostasis. A defect in MAM involved various neurological diseases, including amyotrophic lateral sclerosis (ALS). Recently, we others reported was disrupted models expressing several ALS-linked genes, SOD1, SIGMAR1, VAPB, TARDBP, FUS, suggesting disruption deeply pathomechanism ALS. However, it still uncertain whether common...
The organelle contact site of the endoplasmic reticulum and mitochondria, known as mitochondria-associated membrane (MAM), is a multifunctional microdomain in cellular homeostasis. We previously reported that MAM disruption common pathological feature amyotrophic lateral sclerosis (ALS); however, precise role ALS was uncovered. Here, we show essential for TANK-binding kinase 1 (TBK1) activation under proteostatic stress conditions. A MAM-specific E3 ubiquitin ligase, autocrine motility...
Loss-of-function mutations in TANK-binding kinase 1 (TBK1) are genetically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), induce cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43), known as TDP-43 pathology. Although TBK1 deficiency is thought contribute pathology primarily through impaired autophagy, the full spectrum its pathological impact remains unclear. Given multifunctional nature TBK1, alternative pathways beyond autophagy possibly...