Biology subjects

Oiwa, K.

Publications and source records attributed to Oiwa, K..

3 recordsLinked to original sources

bioRxiv2026

An age-preserving neuronal iSpheroid platform for modeling human aging and Alzheimer disease

Aging is the strongest risk factor for Alzheimer disease (AD), yet existing human neuronal models either erase age-associated features during reprogramming or fail to recapitulate three-dimensional organization of human neuronal tissue. Here, we establish directly induced neuronal spheroids (iSpheroids), a scalable three-dimensional platform generated by direct conversion of primary fibroblasts without pluripotency. iSpheroids generate long-lived, electrophysiologically active neurons from young, unimpaired aged, and sporadic AD donors while preserving donor-specific epigenetic age. Single-nucleus RNA sequencing revealed approximately 96% of cells acquired a neuronal identity and were distributed across multiple neuronal states, including a diversity of neurons. The platform supports incorporation of astrocytes and microglia and generation from non-human primate fibroblasts. AD iSpheroids spontaneously recapitulated neuronal degeneration, amyloid-beta; accumulation, progressive Tau pathology, and metabolic dysfunction. Integrated proteomic, metabolomic, and lipidomic profiling distinguished physiological aging from AD and revealed disease-associated metabolic remodeling. Oxaliplatin shifted AD iSpheroids toward oxidative metabolism, whereas a multi-compound screen identified trametinib as a modulator of inflammatory and age-associated programs.

neuroscience↗

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↗

bioRxiv2017

Small teams of myosin Vc coordinate their stepping for efficient cargo transport on actin bundles

Myosin Vc (myoVc) is unique among vertebrate class V myosin isoforms in that it requires teams of motors to transport cargo. Single molecules of myoVc cannot take multiple steps on single actin filaments, in stark contrast to the well-studied myosin Va (myoVa) isoform. Consistent with in vivo studies (1), only teams of myoVc motors can move continuously on actin bundles at physiologic ionic strength (2), raising the question of how motor-motor interactions cause this preference. Here, using DNA nanostructures as synthetic cargos for linking defined numbers of myoVa or myoVc molecules, we compared the stepping behavior of myoVa versus myoVc teams, and myoVc stepping patterns on single actin filaments versus actin bundles. Run lengths of both myoVa and myoVc teams increased with motor number, but the run lengths of myoVc teams were longer on actin bundles than on filaments. By resolving the stepping behavior of individual myoVc motors with a Qdot bound to the motor domain, we found that coupling of two myoVc molecules significantly decreases futile back/side steps, which were frequently observed for single myoVc motors. Data showing how changes in the inter-motor distance of two coupled myoVc motors affected stepping dynamics suggested that mechanical tension coordinates the stepping behavior of two molecules for efficient directional motion. Our study thus provides a molecular basis to explain how teams of myoVc motors are suited to transport cargos such as zymogen granules on actin bundles.

biophysics↗