記述言語：英語   出版者・発行元：(一社)日本認知症学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by TDP-43 inclusions in the cortical and spinal motor neurons. It remains unknown whether and how pathogenic TDP-43 spreads across neural connections to progress degenerative processes in the cortico-spinal motor circuitry. Here we established novel mouse ALS models that initially induced mutant TDP-43 inclusions in specific neuronal or cell types in the motor circuits, and investigated whether TDP-43 and relevant pathological processes spread across neuronal or cellular connections. We first developed ALS models that primarily induced TDP-43 inclusions in the corticospinal neurons, spinal motor neurons, or forelimb skeletal muscle, by using adeno-associated virus (AAV) expressing mutant TDP-43. We found that TDP-43 induced in the corticospinal neurons was transported along the axons anterogradely and transferred to the oligodendrocytes along the corticospinal tract (CST), coinciding with mild axon degeneration. In contrast, TDP-43 introduced in the spinal motor neurons did not spread retrogradely to the cortical or spinal neurons; however, it induced an extreme loss of spinal motor neurons and subsequent degeneration of neighboring spinal neurons, suggesting a degenerative propagation in a retrograde manner in the spinal cord. The intraspinal degeneration further led to severe muscle atrophy. Finally, TDP-43 induced in the skeletal muscle did not propagate pathological events to spinal neurons retrogradely. Our data revealed that mutant TDP-43 spread across neuro-glial connections anterogradely in the corticospinal pathway, whereas it exhibited different retrograde degenerative properties in the spinal circuits. This suggests that pathogenic TDP-43 may induce distinct antero- and retrograde mechanisms of degeneration in the motor system in ALS.

DOI： 10.1007/s00401-023-02615-8

PubMed

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

Treatments for neurodegenerative disease, including Frontotemporal dementia (FTD) and Amyotrophic lateral sclerosis (ALS), remain rather limited, underscoring the need for greater mechanistic insight and disease-relevant models. Our ability to develop novel disease models of genetic risk factors, disease modifiers, and other FTD/ALS-relevant targets is impeded by the significant amount of time and capital required to develop conventional knockout and transgenic mice. To overcome these limitations, we have generated a novel CRISPRi interference (CRISPRi) knockin mouse. CRISPRi uses a catalytically dead form of Cas9, fused to a transcriptional repressor to knockdown protein expression, following the introduction of single guide RNA against the gene of interest. To validate the utility of this model we have selected the TAR DNA binding protein (TDP-43) splicing target, stathmin-2 (STMN2). STMN2 RNA is downregulated in FTD/ALS due to loss of TDP-43 activity and STMN2 loss is suggested to play a role in ALS pathogenesis. The involvement of STMN2 loss of function in FTD has yet to be determined. We find that STMN2 protein levels in familial FTD cases are significantly reduced compared to controls, supporting that STMN2 depletion may be involved in the pathogenesis of FTD. Here, we provide proof-of-concept that we can simultaneously knock down Stmn2 and express the expanded repeat in the Chromosome 9 open reading frame 72 (C9ORF72) gene, successfully replicating features of C9-associated pathology. Of interest, depletion of Stmn2 had no effect on expression or deposition of dipeptide repeat proteins (DPRs), but significantly decreased the number of phosphorylated Tdp-43 (pTdp-43) inclusions. We submit that our novel CRISPRi mouse provides a versatile and rapid method to silence gene expression in vivo and propose this model will be useful to understand gene function in isolation or in the context of other neurodegenerative disease models.

DOI： 10.3389/fcell.2023.1251551

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Public Library of Science (PLoS)  

A major function of TAR DNA-binding protein-43 (TDP-43) is to repress the inclusion of cryptic exons during RNA splicing. One of these cryptic exons is in UNC13A, a genetic risk factor for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The accumulation of cryptic UNC13A in disease is heightened by the presence of a risk haplotype located within the cryptic exon itself. Here, we revealed that TDP-43 extreme N-terminus is important to repress UNC13A cryptic exon inclusion. Further, we found hnRNP L, hnRNP A1, and hnRNP A2B1 bind UNC13A RNA and repress cryptic exon inclusion, independently of TDP-43. Finally, higher levels of hnRNP L protein associate with lower burden of UNC13A cryptic RNA in ALS/FTD brains. Our findings suggest that while TDP-43 is the main repressor of UNC13A cryptic exon inclusion, other hnRNPs contribute to its regulation and may potentially function as disease modifiers.

DOI： 10.1371/journal.pbio.3002028

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective degeneration of upper and lower motor neurons. Currently, there are no effective biomarkers and fundamental therapies for this disease. Dysregulation in RNA metabolism plays a critical role in the pathogenesis of ALS. With the contribution of Next Generation Sequencing, the functions of non-coding RNAs (ncRNAs) have gained increasing interests. Especially, micro RNAs (miRNAs), which are tissue-specific small ncRNAs of about 18-25 nucleotides, have emerged as key regulators of gene expression to target multiple molecules and pathways in the central nervous system (CNS). Despite intensive recent research in this field, the crucial links between ALS pathogenesis and miRNAs remain unclear. Many studies have revealed that ALS-related RNA binding proteins (RBPs), such as TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS), regulate miRNAs processing in both the nucleus and cytoplasm. Of interest, Cu2+/Zn2+ superoxide dismutase (SOD1), a non-RBP associated with familial ALS, shows partially similar properties to these RBPs via the dysregulation of miRNAs in the cellular pathway related to ALS. The identification and validation of miRNAs are important to understand the physiological gene regulation in the CNS, and the pathological implications in ALS, leading to a new avenue for early diagnosis and gene therapies. Here, we offer a recent overview regarding the mechanism underlying the functions of multiple miRNAs across TDP-43, FUS, and SOD1 with the context of cell biology, and challenging for clinical applications in ALS.

DOI： 10.3389/fnins.2023.1131758

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media {LLC}  

<jats:title>Abstract</jats:title><jats:p>Frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) is a neurodegenerative disease primarily affecting the frontal and/or temporal cortices. However, a growing body of evidence suggests that the cerebellum contributes to biochemical, cognitive, and behavioral changes in FTLD-TDP. To evaluate cerebellar TDP-43 expression and function in FTLD-TDP, we analyzed TDP-43 protein levels and the splicing of a TDP-43 target, <jats:italic>STMN2</jats:italic>, in the cerebellum of 95 FTLD-TDP cases and 25 non-neurological disease controls. Soluble TDP-43 was decreased in the cerebellum of FTLD-TDP cases but a concomitant increase in insoluble TDP-43 was not seen. Truncated <jats:italic>STMN2</jats:italic> transcripts, an indicator of TDP-43 dysfunction, were elevated in the cerebellum of FTLD-TDP cases and inversely associated with TDP-43 levels. Additionally, lower cerebellar TDP-43 associated with a younger age at disease onset. We provide evidence of TDP-43 loss of function in the cerebellum in FTLD-TDP, supporting further investigation into this understudied brain region.</jats:p>

DOI： 10.1186/s40478-022-01408-6

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1126/science.abq7860

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/ctm2.818

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41586-022-04424-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Activation of human endogenous retrovirus-K (HERV-K) is one of the proposed risk factors for amyotrophic lateral sclerosis (ALS). The HERV-K envelope protein has been reported to show neurotoxicity, and development of therapy with reverse transcriptase inhibitors is being investigated. On the other hand, some reports have failed to show HERV-K activation in ALS. In this study, we analyzed the expression of HERV-K mRNA in the motor cortex and spinal cord of 15 Japanese patients with sporadic ALS and 19 controls using reverse transcriptase droplet digital PCR. This revealed no significant increase of HERV-K expression in ALS-affected tissues, suggesting that the association between ALS and HERV-K remains questionable.

DOI： 10.1016/j.neures.2022.01.009

PubMed

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記述言語：英語   出版者・発行元：(一社)日本認知症学会  

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cold Spring Harbor Laboratory  

<title>Abstract</title>In amyotrophic lateral sclerosis (ALS), TAR DNA-binding protein 43 (TDP-43) forms aggregates in the motor cortex of the aging brain. This aggregate formation may be triggered by the increase in TDP-43 levels with aging. However, the amount of TDP-43 is autoregulated by the alternative splicing of the <italic>TARDBP</italic> 3’UTR, and its relationship with aging remains unresolved. Since DNA methylation is altered during aging, we hypothesized that 3’UTR methylation is also altered in the aging motor cortex, disrupting this autoregulatory system and increasing TDP-43 levels. We found that DNA demethylation in the autoregulatory region of TDP-43 reduced alternative splicing and increased TDP-43 expression. Furthermore, in the human motor cortex, we found that this region was demethylated with age and that the expression of TDP-43 increased. The dysregulation of TDP-43 autoregulation by age-related DNA demethylation in the motor cortex may explain the contribution of aging and system selectivity in ALS.

DOI： 10.1038/s42003-021-02621-0

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.parkreldis.2021.07.018

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(公財)金原一郎記念医学医療振興財団  

＜文献概要＞副腎白質ジストロフィーは,ABCD1遺伝子変異により生じる先天代謝異常症である。生化学的には極長鎖脂肪酸の蓄積を,病理学的には中枢神経系の脱髄を特徴とするが,その疾患メカニズムは完全には解明されておらず,今なお病態研究は進行中である。一方で,治療に関しては,発症早期における造血幹細胞の移植や遺伝子治療の有効性が示されており,今後ますます早期診断,早期介入の必要性が高まることが想定される。

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

孤発性筋萎縮性側索硬化症(sporadic amyotrophic lateral sclerosis;SALS)、および多くの家族性ALS(familial ALS;FALS)において、神経細胞質内transactive response DNA-binding protein 43kDa(TDP-43)陽性の封入体を認める。この事実からTDP-43は本症の根幹に関わる分子である。ALS病因遺伝子の機能解析から、TDP-43の病的凝集体形成/分解に関わる発症メカニズムの解明が進められている。凝集体形成の場として、非膜性構造であるストレス顆粒が注目されており、FUSやC9orf72の関与が示されている。一方、凝集体分解機構であるユビキチン-プロテアソーム系、オートファジー系に関わるALS病因遺伝子も報告されている。SALSおよびFALSに共通する分子病態に対する治療研究が進められている。(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.5692/clinicalneurol.cn-001362

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by accumulation of fragmented insoluble TDP-43 and loss of TDP-43 from the nucleus. Increased expression of exogenous TARDBP (encoding TDP-43) induces TDP-43 pathology and cytotoxicity, suggesting the involvement of aberrant expression of TDP-43 in the pathogenesis of ALS. In normal conditions, however, the amount of TDP-43 is tightly regulated by the autoregulatory mechanism involving alternative splicing of TARDBP mRNA. To investigate the influence of autoregulation dysfunction, we inhibited the splicing of cryptic intron 6 using antisense oligonucleotides in vivo. This inhibition doubled the Tardbp mRNA expression, increased the fragmented insoluble TDP-43, and reduced the number of motor neurons in the mouse spinal cord. In human induced pluripotent stem cell-derived neurons, the splicing inhibition of intron 6 increased TARDBP mRNA and decreased nuclear TDP-43. These non-genetically modified models exhibiting rise in the TARDBP mRNA levels suggest that TDP-43 autoregulation turbulence might be linked to the pathogenesis of ALS.

DOI： 10.1016/j.nbd.2019.104534

PubMed

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記述言語：英語   出版者・発行元：(一社)日本てんかん学会  

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記述言語：日本語   出版者・発行元：(株)羊土社  

TDP-43やFUSに代表される、筋萎縮性側索硬化症(ALS)関連タンパク質の多くは、RNA結合タンパク質であり、複数の生体高分子と凝集し、非膜性の集合体を形成する。この現象は液-液相分離(LLPS)とよばれる。LLPSと類似の挙動を呈する非膜性の細胞構造の一つであるGEM小体は、スプライソソーム成熟に寄与する。われわれは、TDP-43発現抑制細胞とALS患者由来組織において、GEM小体数減少を示した。このことは、ALS関連タンパク質の機能喪失により、スプライソソーム機能不全を介したスプライシング破綻が生じることを示す。(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: The prognosis of adrenoleukodystrophy (ALD)with neurological involvement is generally dismal; however, allogeneic stem cell transplantation (SCT) is recognized as effective to stabilize or improve the clinical symptoms of ALD. Herein, we report the clinical outcomes of patients with ALD who consecutively underwent allogeneic stem cell transplantation with reduced intensity conditioning at our institution. Patients: Sixteen patients with ALD, who were symptomatic (n = 14) or presymptomatic (n = 2), received SCT from 2010 to 2016. The stem cell source was cord blood (n = 14), or bone marrow from a human leukocyte antigen identical sibling (n = 2). The conditioning regimen prior to transplantation was reduced intensity and consisted of fludarabine (125 mg/m2), melphalan (140 mg/m2) and low dose total body irradiation (TBI) of 4Gy (n = 15) or 3Gy (n = 1). Results: Primary engraftment was obtained in 11 patients, and 4 of the 5 patients who lost the primary graft received a second cord blood transplantation and were engrafted. Five years overall and event-free survival were 90.9% and 61.1% respectively, with a median of 45 months (range 16-91). Loes score stabilized or improved by 18 months after transplantation except for patients with internal capsule involvement. Conclusion: Allogeneic SCT with reduced intensity conditioning for patients with ALD was safely performed without major transplant-related complications even in symptomatic patients and neurological symptoms were stabilized after SCT in patients without internal capsule involvement.

DOI： 10.1016/j.ymgmr.2018.11.001

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm and its disappearance from the nucleus are pathological features of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) and are directly involved in the pathogenesis of these conditions. TDP-43 is an essential nuclear protein that readily aggregates in a concentration-dependent manner. Therefore, cells must strictly maintain an appropriate amount of nuclear TDP-43. In one relevant maintenance mechanism, TDP-43 binds to its pre-mRNA and promotes alternative splicing, resulting in mRNA degradation via nonsense-mediated mRNA decay. The level of nuclear TDP-43 is tightly regulated by these mechanisms, which control the amount of mRNA that may be translated. Based on the results of previous experiments, we developed an in silico model that mimics the intracellular dynamics of TDP-43 and examined TDP-43 metabolism under various conditions. We discovered an inherent trade-off in this mechanism between transcriptional redundancy, which maintains the robustness of TDP-43 metabolism, and vulnerability to specific interfering factors. These factors include an increased tendency of TDP-43 to aggregate, impaired nuclear-cytoplasmic TDP-43 transport, and a decreased efficiency of degrading abnormal proteins, all of which are functional abnormalities related to the gene that causes familial ALS/FTD. When these conditions continue at a certain intensity, the vulnerability of the autoregulatory machinery becomes apparent over time, and transcriptional redundancy enters a vicious cycle that ultimately results in TDP-43 pathology. The results obtained using this in silico model reveal the difference in TDP-43 metabolism between normal and disease states. Furthermore, using this model, we simulated the effect of a decrease in TDP-43 transcription and found that this decrease improved TDP-43 pathology and suppressed the abnormal propagation of TDP-43. Therefore, we propose a potential therapeutic strategy to suppress transcriptional redundancy, which is the driving force of the pathological condition caused by the specific factors described above, in patients with ALS presenting with TDP-43 pathology. An ALS animal model exhibiting TDP-43 pathology without overexpression of exogenous TDP-43 should be developed to investigate the effect of alleviating the transcriptional redundancy of TARDBP.

DOI： 10.3389/fnins.2018.00028

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/ncn3.12067

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Objective: Fifty percent of patients with amyotrophic lateral sclerosis (ALS) have cervical spondylotic myelopathy (CSM) as a complication. Because patients with ALS do not develop bulbar signs and symptoms at onset, differentiating them from patients with CSM is sometimes difficult. We aimed to determine whether the apparent diffusion coefficients (ADCs) of intracranial corticospinal tracts can be used to distinguish between patients with ALS and those with CSM.
Methods: We evaluated 19 consecutive patients with ALS who did not have CSM by cervical MRI, 16 patients with CSM, and 11 healthy controls. We examined the mean ADCs in the precentral gyrus, the corona radiata, the posterior limbs of the internal capsule (PLIC), and the cerebral peduncle by 3T magnetic resonance imaging (MRI). The mean ADCs in the intracranial corticospinal tracts in patients with ALS were compared with those in patients with CSM.
Results: The mean ADCs in the intracranial corticospinal tracts in patients with ALS were compared with those in patients with CSM (p&lt;0.05). Additionally, the mean ADCs in the precentral gyrus, the PLIC, and the cerebral peduncle in the patients with ALS, including the patients who were initially diagnosed as having clinically possible ALS on the basis of the revised El Escorial criteria and did not develop bulbar symptoms at onset, were also higher than those in patients with CSM (p&lt;0.05).
Conclusions: Elevated ADCs in the intracranial corticospinal tracts might be useful for distinguishing ALS from CSM in the early stage of the disease. (C) 2015 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.clineuro.2015.02.009

Web of Science

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：(一社)日本神経学会  

症例は1型糖尿病と診断されている62歳の女性である。発熱後、亜急性に両下肢筋力低下、尿閉をきたして入院した。頸部・上肢の筋強剛と上肢ミオクローヌス、感覚性運動失調をみとめた。血清抗GAD抗体、抗TPO抗体、抗ミトコンドリアM2抗体、抗glycine受容体抗体が陽性であり、多腺性自己免疫症候群を背景に発症した、progressive encephalomyelitis with rigidity and myoclonus(PERM)と診断した。経過中、末梢神経障害が出現し、抗GM1抗体が陽性であった。本例は多様な抗体が病態に関与し、従来のPERMの臨床像を超えた多彩な神経症状をきたした症例である。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J01550&link_issn=&doc_id=20150512350007&doc_link_id=130004921314&url=http%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F130004921314&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.5692/clinicalneurol.55.111

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.5692/clinicalneurol.cn-000682

Scopus

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/ncn3.116

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記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/ncn3.74

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掲載種別：研究論文（学術雑誌）  

Amyloid-β-related angiitis (ABRA) of the CNS occurs in association with vasculitis of small-and medium-sized leptomeningeal arteries. Here, we describe the clinicopathological features of a 76-year-old man with ABRA. The patient suffered progressive truncal oscillation, aphasia, and recent memory disturbance with a subacute disease onset. His cerebrospinal fluid showed a mild increase in protein levels (101 mg/dL) and pleocytosis (8/mm(3)). High-intensity brain lesion were detected on T(2)-weighted and FLAIR MRI scans, and prominent spread of gadolinium enhancement spreading was observed through the sulci of the left occipital and temporal lobes and left cerebellar hemisphere. A biopsy of the left temporal lesion showed a granulomatous and angiodestructive inflammation with infiltration of many CD4(+) T-lymphocytes and multinucleated giant cells and with fibrinoid necrosis of the arterial walls in the subarachnoid space. Immunolabeling for Aβ(1-40) revealed the abundant deposition of this protein in the affected arteries. On the basic of the diagnosis of ABRA, immunosuppressive therapy was conducted, and it ameliorated the clinical course.

PubMed

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(有)科学評論社  

機能性RNAの中の代表的なものに、転移RNA、リボソームRNAなどがある。これらは、それぞれ翻訳において重要な役割を有する。この機能性RNAの一種にuridine rich small nuclear RNA(UsnRNA)がある。細胞内のmRNAや機能性RNAの量的、質的な多様性、恒常性のことをribostasisと称し、筋萎縮性側索硬化症(ALS)の病態機序との関連が注目されている。RNA代謝の中で、UsnRNAおよびUsnRNAの成熟に関わる核内の構造物であるGemini of coiled bodyとALSとの関連について最新の知見を述べた。

J-GLOBAL

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記述言語：日本語   出版者・発行元：日本赤十字社医学会  

CiNii Article

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記述言語：日本語   出版者・発行元：日本赤十字社医学会  

CiNii Article

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記述言語：日本語   出版者・発行元：日本赤十字社医学会  

CiNii Article

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

CiNii Article

CiNii Books

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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