Biology subjects

Horiuchi, M.

Publications and source records attributed to Horiuchi, M..

4 recordsLinked to original sources

bioRxiv2025

TBK1 eliminates aggregation-prone monomeric TDP-43 through the IFNβ-immunoproteasome pathway

Loss-of-function mutations in TANK-binding kinase 1 (TBK1) are genetically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and induce cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43), known as TDP-43 pathology. Although TBK1 deficiency is thought to contribute to TDP-43 pathology primarily through impaired autophagy, the full spectrum of its pathological impact remains unclear. Given the multifunctional nature of TBK1, alternative pathways beyond autophagy are possibly involved in TDP-43 pathology. Here, we found that TBK1 alleviates TDP-43 pathology in neuronal cells via induction of interferon-beta (IFN{beta}), and that the IFN{beta} receptor is downregulated in spinal motor neurons from ALS patients with TDP-43 pathology. We further demonstrated that IFN{beta} induces the immunoproteasome by upregulating its subunits, thereby promoting the degradation of aggregation-prone monomeric TDP-43. Furthermore, heterozygous deletion of Tbk1 in SOD1G93A ALS model mice resulted in reduced immunoproteasome induction and increased polyubiquitinated protein accumulation in the spinal cord. These findings suggest that impairment of the TBK1-IFN{beta}-immunoproteasome axis may contribute to the development of TDP-43 pathology in ALS and FTD.

neuroscience↗

bioRxiv2024

Speed amplitude and period affect gait variability and step followability under sinusoidal speed changing conditions

BackgroundThe time courses of the joint elevation angles of the thigh, shank, and foot in one stride during walking can be well approximated by a "plane" in a triaxial space. This intersegmental coordination (IC) of the lower limb elevation angles is called planar covariation law. Thickness of the IC plane is associated with gait variability. This study aimed to examine how anteroposterior and lateral gait variabilities are influenced by sinusoidal speed changes with different amplitudes ({+/-}0.33 vs. {+/-}0.67 m{middle dot}s-1) and periods (30 vs. 60 s). We also questioned which limbs are responsible for the step variabilities in these conditions. MethodsEighteen young adults walked on a treadmill under sinusoidal speed-changing conditions with different amplitudes ({+/-}0.33 vs. {+/-}0.67 m{middle dot}s-1) and periods (30-vs. 60-s). Using 3D motion analysis system, we quantified the IC plane thickness, coefficient of variance of step width (CVSW), time delay of step length (TDSL), and step frequency (TDSF). We applied 2-way statistical parametric mapping for the time courses of each limb angle during the acceleration and deceleration phases. ResultsThe IC plane thickness was greater in the {+/-}0.67 m{middle dot}s-1 condition than in the {+/-}0.33 m{middle dot}s-1 condition. Periods and amplitudes did not affect CVSW, TDSL, and TDSF. In the middle gait cycle, the thigh and shank were delayed in the greater amplitude condition during the acceleration phase but proceeded in the same condition during the deceleration phase. DiscussionSinusoidal speed amplitude influenced anteroposterior gait variability, but not lateral gait variability, regardless of period, even in healthy young adults. More distal limbs were delayed in the greater speed amplitude condition during the acceleration phase, whereas more proximal limbs proceeded in that condition during the deceleration phase, indicating that these different behaviors of the lower limb segments could be related to step variabilities.

physiology↗

bioRxiv2021

Intranasal gene therapy to prevent infection by SARS-CoV-2 variants

SARS-CoV-2 variants have emerged with enhanced pathogenicity and transmissibility, and escape from pre-existing immunity, suggesting first-generation vaccines and monoclonal antibodies may now be less effective. This manuscript demonstrates an approach for preventing clinical sequelae and the spread of SARS-CoV-2 variants. First, we affinity-matured an angiotensin-converting enzyme 2 (ACE2) decoy protein, achieving 1000-fold binding improvements that extend across a wide range of SARS-CoV-2 variants and distantly related, ACE2-dependent coronaviruses. Next, we demonstrated the expression of this decoy in proximal airway when delivered via intranasal administration of an AAV vector. This intervention significantly diminished clinical and pathologic consequences of SARS-CoV-2 challenge in a mouse model and achieved therapeutic levels of decoy expression at the surface of proximal airways when delivered intranasally to nonhuman primates. Importantly, this long-lasting, passive protection approach is applicable in vulnerable populations such as the elderly and immune-compromised that do not respond well to traditional vaccination. This approach could be useful in combating COVID-19 surges caused by SARS-CoV-2 variants and should be considered as a countermeasure to future pandemics caused by pre-emergent members, ACE2-dependent CoVs that are poised for zoonosis. Author summarySARS-CoV-2 variants have emerged with enhanced pathogenicity and transmissibility, and escape from pre-existing immunity, suggesting first-generation vaccines and monoclonal antibodies may now be less effective. This manuscript demonstrates an approach for preventing clinical sequelae and the spread of SARS-CoV-2 variants. First, we affinity-matured an angiotensin-converting enzyme 2 (ACE2) decoy protein, achieving 1000-fold binding improvements that extend across a wide range of SARS-CoV-2 variants and distantly related, ACE2-dependent coronaviruses. Next, we demonstrated the expression of this decoy in proximal airway when delivered via intranasal administration of an AAV vector. This intervention significantly diminished clinical and pathologic consequences of SARS-CoV-2 challenge in a mouse model and achieved therapeutic levels of decoy expression at the surface of proximal airways when delivered intranasally to nonhuman primates. Importantly, this long-lasting, passive protection approach is applicable in vulnerable populations such as the elderly and immune-compromised that do not respond well to traditional vaccination. This approach could be useful in combating COVID-19 surges caused by SARS-CoV-2 variants and should be considered as a countermeasure to future pandemics caused by pre-emergent members, ACE2-dependent CoVs that are poised for zoonosis.

genetics↗

bioRxiv2020

Activation of prodynorphin neurons in the dorsomedial hypothalamus inhibits food intake and promotes positive valence

The regulation of food intake is one of the major research areas in the study of metabolic syndromes such as obesity. Gene targeting studies have clarified the roles of hypothalamic neurons in feeding behaviour. However, our understanding of neural function under physiological conditions is still limited. Immediate early genes, such as activity-regulated cytoskeleton-associated protein (Arc/Arg3.1), are useful markers of neuronal activity. Here, we investigated the role of Arc/Arg3.1 gene-expressing neurons in the hypothalamus after refeeding using the targeted recombination in active populations method. We identified refeeding-responsive prodynorphin/cholecystokinin neurons in the dorsomedial hypothalamus that project to the paraventricular hypothalamic nucleus. Chemogenetic activation of these neurons decreased food intake and promoted positive valence. Our findings provide insight into the role of newly identified hedonic neurons in the process of feeding-induced satiety.

physiology↗