記述言語：英語   掲載種別：研究論文（学術雑誌）  

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) develop as spatial pathologies in which neurons and glial cells are interconnected. TAR DNA-binding protein 43 (TDP-43) is a major pathological protein that is inextricably associated with ALS and FTLD. In this study, we investigated the roles of neuronal TDP-43 in neuron-oligodendrocyte interactions using neuron-specific TDP-43 knockout (TDP-43cKO) mice. TDP-43 depletion in neurons induced hypomyelination, which was confirmed by immunohistochemistry and ultrastructural analysis. In addition, conduction disturbance was revealed by electrophysiological analysis. The hypomyelination of TDP-43cKO mouse was restored by cytoplasmic TDP-43 supplementation in neurons. Neuron-specific transcriptome analysis revealed that neurexin 1 (NRXN1) is the regulatory target of TDP-43, which promotes myelin formation. The hypomyelination of TDP-43cKO mice was also restored by NRXN1b supplementation in neurons. We further confirmed that TDP-43 stabilizes Nrxn1 mRNA by binding to the Nrxn1 3'untranslated region (3'UTR). Although TDP-43cKO exhibited impaired recognition memory, the supplementation of NRXN1 in the hippocampus recovered the memory disturbances. In conclusion, this study demonstrates the neuron-oligodendrocyte interaction mediated by neuronal TDP-43 via NRXN1 mRNA stabilization. These findings shed light on neuron-oligodendrocyte interaction in the disease mechanisms of ALS/FTLD.

DOI： 10.1073/pnas.2513642123

Open Access

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

TAR-binding protein 43 (TDP-43) is a pathogenic RNA-binding protein associated with amyotrophic lateral sclerosis (ALS). To elucidate the pathogenesis of ALS, we generated induced pluripotent stem cells (iPSCs) from lymphoblastoid cell line (LCL) cells of an ALS patient with the TDP-43I383V heterozygous mutation. Furthermore, we generated isogenic wild-type iPSCs from wild-type LCL cells using scarless genome editing with CRISPR/Cas9. A modified iPSC-derived motor neuron culture method utilizing BrainPhys neuronal medium and rat astrocyte co-culture effectively promoted and maintained neuronal activity. Under these conditions, the TDP-43I383V heterozygous mutation resulted in increased TDP-43 protein expression through prolonged stabilization. Moreover, mutant iPSC-derived motor neurons showed increased numbers of pre-synapses and altered neuronal activity. These results suggest that the modified motor neuron culture method can help elucidate abnormalities in TDP-43 expression, synapse formation, and neuronal activity caused by the heterozygous TDP-43I383V mutation. The model developed in this study has the potential to facilitate the analysis of the early pathological phenotype of ALS.

DOI： 10.1016/j.neures.2025.105003

Open Access

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease characterized by progressive ptosis and ophthalmoplegia, caused by single deletions, point mutations, or multiple deletions in mitochondrial DNA (mtDNA). Most point mutations occur in tRNA genes. Here, we report a novel variant of the tRNAGlu gene associated with CPEO. A 45-year-old male presented with ptosis and external ophthalmoplegia; however, blood test results, including lactate levels and autoantibodies, were normal. CPEO was suspended, prompting additional myopathological examination, mtDNA sequencing analysis, long polymerase chain reaction (PCR) analysis, and single-fiber analysis to compare mutation loads between ragged-red fibers (RRFs) and non-RRFs. Histopathological examination revealed scattered COX-negative RRFs. No deletions were found in the mtDNA. MtDNA sequencing analysis revealed a novel variant, m.14677 T > C, in the tRNAGlu gene, with Sanger sequencing indicating 45% heteroplasmy in the muscle tissue. Single-fiber analysis showed a significantly higher mutation load of m.14677 T > C in RRFs (range: 25.3-92.8%; median: 88.1%; n = 6) compared with non-RRFs (range: 3.5-85.9%; median: 17.1%; n = 5) (P = 0.03). Based on the significantly higher mutation load in RRFs than in non-RRFs, pathological evidence of mitochondrial disease, and the mutation's occurrence at an evolutionarily conserved site, we concluded that m.14677 T > C, a novel variant of the tRNAGlu gene, is the cause of CPEO. Biochemical and histopathological examinations of muscle tissue, combined with single-fiber analysis, are valuable tools for evaluating mtDNA variants, particularly those within tRNA genes.

DOI： 10.1038/s10038-025-01381-7

Open Access

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

TAR DNA-binding protein 43 (TDP-43)-positive cytoplasmic aggregation is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). This aggregation contributes substantially to the neurodegeneration of ALS and FTLD. The endosome, a key component of membrane trafficking in eukaryotic cells and is involved in the autophagy-lysosome pathway. Endosome-related genes such as CHMP2B, Alsin, and TMEM106B, are either causative or act as genetic modifiers in ALS and FTLD. However, the association between endosomal functions and TDP-43 aggregations remain poorly understood. The C-terminal truncation mutation CHMP2B, which causes frontotemporal dementia associated with chromosome 3 (FTD3), disrupts late endosome (LE)-lysosomes fusion. Nevertheless, FTD3 does not induce TDP-43 pathology. In this study, we showed that CHMP2B mutation-induced LE dysfunction promotes TDP-43 aggregate degradation through enhanced recruitment to juxtanuclear quality control compartments. Transcriptomic analysis revealed that CHMP2Bintron5 overexpression upregulates HSP70 expression. New insights into the connection between CMHP2B and HSP70 as well as the role of HSP70-mediated membrane trafficking in TDP-43 aggregation, offer a valuable understanding of the disease mechanism of ALS and FTLD.

DOI： 10.1016/j.neuint.2025.105982

Open Access

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

TAR DNA-binding protein 43 (TDP-43) is of particular interest in the pathogenesis of amyotrophic lateral sclerosis (ALS). It has been speculated that loss of nuclear TDP-43 and its cytoplasmic aggregation contributes to neurodegeneration. Although considerable attention has been paid to RNA metabolism in TDP-43 function, TDP-43 is also known to act as a transcription factor. This study found that the expression of Nuclear-enriched abundant transcript 1 (NEAT1), a long-non-coding RNA, was substantially downregulated in motor neurons with nuclear TDP-43 loss, but upregulated in those with preserved nuclear TDP-43, in the postmortem spinal cords of patients with sporadic ALS. TDP-43 depletion induced Neat1 downregulation in Neuro2a cells, primary cortical neurons, and mouse spinal motor neurons. Furthermore, TDP-43 was found to positively regulate NEAT1 at the transcriptional level. Finally, Neat1 knockout exacerbates neurodegeneration of hSOD1G93A mice accompanied by increased misfolded superoxide dismutase 1 (SOD1) aggregations. Transcriptome analysis revealed that Neat1 knockout reduced protein folding-related genes, such as heat shock protein family A member 1A (Hspa1a), in the spinal cords of hSOD1G93A mice. Our results indicated that the loss of TDP-43 function enhances ALS neurodegeneration by losing the protective effect of NEAT1.

DOI： 10.1093/braincomms/fcaf261

Open Access

PubMed

J-GLOBAL

開催年月日： 2025年3月

記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

開催地：名古屋大学東山キャンパス  

開催年月日： 2024年7月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：熊本大学発生医学研究所  

開催年月日： 2024年5月 - 2024年6月

記述言語：英語   会議種別：ポスター発表  

開催年月日： 2024年4月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：名古屋大学大幸キャンパス