Language：English   Publisher：(一社)日本認知症学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Myositis generally affects the proximal muscles. However, we herein report a case of a 48-year-old woman with intractable myositis affecting the intrinsic muscles of the hands. Her myositis, which developed in childhood, was refractory to treatment with steroids and several immunosuppressants, causing walking disability. After experiencing pain and swelling in the hands for six months, she was diagnosed with myositis of the intrinsic muscles of the hands and tested positive for the anti-signal recognition particle antibody. Intravenous immunoglobulin therapy improved the myositis of the hands. This case suggests that inflammation caused by intractable myositis can extend to the hands.

DOI： 10.2169/internalmedicine.3773-19

PubMed

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Language：Japanese   Publishing type：Research paper (scientific journal)  

In amyloid β-related angiitis, cortical or subcortical microbleeding or cortical superficial siderosis supports clinical diagnosis. However, here we present a 75-year-old female case of amyloid β-related angiitis that did not initially show these lesions. The patient developed right homonymous hemianopia and aphasia, and subsequently became comatose. Her brain lesions progressed extensively from the left occipital lobe to the bilateral cerebral hemispheres, with diffused leptomeningeal lesions and scattered DWI high-intensity lesions. After pathological diagnosis, steroid treatment improved her symptoms as well as imaging findings. No hemorrhagic lesions were detected in the T2*-weighted imaging performed before treatment. However, susceptibility-weighted imaging performed after treatment showed a number of lesions with microbleeding. The clinical features of amyloid β-related angiitis that do not show hemorrhagic lesions at onset should be investigated for rapid therapeutic intervention in the future.

DOI： 10.5692/clinicalneurol.cn-001340

PubMed

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Language：Japanese   Publisher：(一社)日本神経学会  

アミロイドβ関連血管炎(amyloid β-related angiitis)では、皮質や皮質下の微小出血や脳表ヘモジデリンの沈着が、脳MRI上の重要な所見である。我々は、治療前にはこれらの所見を呈さなかったアミロイドβ関連血管炎を提示する。症例は75歳女性。右同名半盲と失語で発症し、昏睡に至った。脳MRIでは、びまん性の軟髄膜造影病変と散在性のDWI高信号病変を認めたが、T2*WIでは微小出血は検出されなかった。病理所見からアミロイドβ関連血管炎と診断した。ステロイド治療により画像所見、臨床症状ともに改善した。治療後のsusceptibility-weighted imaging(SWI)では多数の微小出血を認めた。アミロイドβ関連血管炎の非侵襲的診断のために、微小出血以外の画像の特徴を集積すべきである。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01550&link_issn=&doc_id=20200310190003&doc_link_id=130007822832&url=http%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F130007822832&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

Language：Japanese   Publishing type：Research paper (scientific journal)  

Sporadic amyotrophic lateral sclerosis (SALS) and many cases of familial ALS (FALS) demonstrate cytoplasmic transactive response DNA-binding protein 43 kDa (TDP-43)-positive inclusion bodies. Thus, TDP-43 plays a vital role in ALS pathogenesis. Functional analysis of the ALS causative genes advanced the elucidation of the mechanism associated with the formation and degradation of TDP-43 aggregates. Stress granules, which are non-membranous organelles, are attracting attention as sites of aggregate formation, with involvement of FUS and C9orf72. Concurrently, ALS causative genes related to the ubiquitin-proteasome and autophagy systems, which are aggregate degradation mechanisms, have also been reported. Therefore, therapeutic research based on the molecular pathology common to SALS and FALS has been advanced.

DOI： 10.5692/clinicalneurol.cn-001362

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Language：Japanese   Publisher：(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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Language：English   Publisher：新潟医学会  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00990&link_issn=&doc_id=20201223020014&doc_link_id=%2Fdg3nigta%2F2019%2Fs13311%2F007%2F0391-0391%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2019%2Fs13311%2F007%2F0391-0391%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞TDP-43蛋白質の封入体形成機構は,筋萎縮性側索硬化症(ALS)の主要な分子病態機序である。ALS原因遺伝子の機能解析から,TDP-43封入体形成にはストレス顆粒形成,蛋白質分解機構,TDP-43蛋白質の自己調節機構の破綻などが関わることが見出された。これらの解明された分子病態に基づく,ALS治療方法の確立が期待される。

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Language：Japanese   Publishing type：Research paper (scientific journal)  

The molecular pathogenesis of amyotrophic lateral sclerosis (ALS) has been studied through analysis of the function of the protein produced by the causative genes of familial ALS. The products of these genes are classified as RNA binding proteins, or proteins related to proteolytic systems. However, most case of familial ALS, and sporadic ALS show TAR DNA binding protein-43 (TDP-43) immune-positive cytoplasmic inclusions. Therefore, the molecular mechanism of formation of TDP-43 inclusions and dysfunction caused by TDP-43 inclusions has been studied. As for the mechanism of inclusion formation, non-membrane organelle formation by liquid-liquid phase separation (LLPS) is important. The ubiquitin-proteasome and autophagy systems are important for the degradation of these inclusions. Several genes associated with these systems have been identified as causative genes for ALS. The formation of cytoplasmic inclusions results in the loss of TDP-43 from the nucleus, resulting in abnormalities in RNA metabolism, through the alteration of spliceosomes and Gemini of coiled bodies. Furthermore, in ALS, the regulation of TDP-43 mRNA/protein expression levels has failed. Failure of the autoregulation system facilitates TDP-43 inclusion formation. Development of treatments for ALS based on these elucidated molecular mechanisms is desirable.

DOI： 10.11477/mf.1416201428

PubMed

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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

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Language：Japanese   Publisher：(株)ニュー・サイエンス社  

神経変性疾患を特徴づける脳内に異常に蓄積するタンパク質には、RNA結合タンパク質が多く含まれる。RNA結合タンパク質は、タンパク質をコードするmRNAのみならず、mRNA前駆体のイントロン領域や非翻訳領域、さらにはノンコーディングRNAに対しても結合し、広範な細胞内機能を担っている。特定の脳タンパク質が異常に蓄積する神経変性疾患の病態を理解し、これを制御するためには、RNA結合タンパク質とこれと関連するRNA代謝の両面からのアプローチが必要となる。近年、RNA結合タンパク質とその標的RNAの量の不均衡が細胞毒性と関連することを示唆する報告が集まりつつある。RNA結合タンパク質と関連するRNAからなるロバストな細胞内制御機構の背後に潜む脆弱因子を特定し、制御することが、これらの脳疾患の克服につながるものと期待したい。(著者抄録)

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder. In motor neurons of ALS, TAR DNA binding protein-43 (TDP-43), a nuclear protein encoded by TARDBP, is absent from the nucleus and forms cytoplasmic inclusions. TDP-43 auto-regulates the amount by regulating the TARDBP mRNA, which has three polyadenylation signals (PASs) and three additional alternative introns within the last exon. However, it is still unclear how the autoregulatory mechanism works and how the status of autoregulation in ALS motor neurons without nuclear TDP-43 is. Here we show that TDP-43 inhibits the selection of the most proximal PAS and induces splicing of multiple alternative introns in TARDBP mRNA to decrease the amount of cytoplasmic TARDBP mRNA by nonsense-mediated mRNA decay. When TDP-43 is depleted, the TARDBP mRNA uses the most proximal PAS and is increased in the cytoplasm. Finally, we have demonstrated that in ALS motor neurons-especially neurons with mislocalized TDP-43-the amount of TARDBP mRNA is increased in the cytoplasm. Our observations indicate that nuclear TDP-43 contributes to the autoregulation and suggests that the absence of nuclear TDP-43 induces an abnormal autoregulation and increases the amount of TARDBP mRNA. The vicious cycle might accelerate the disease progression of ALS.

DOI： 10.1093/nar/gkw499

Web of Science

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMJ Publishing Group  

Background A GGGGCC hexanucleotide repeat expansion in C9ORF72 occurs on a chromosome 9p21 locus that is linked with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in white populations. The diseases resulting from this expansion are referred to as 'c9FTD/ALS'. It has been suggested that c9FTD/ALS arose from a single founder. However, the existence of c9FTD/ALS in non-white populations has not been evaluated. Results We found two index familial ALS (FALS) patients with c9FTD/ALS in the Japanese population. The frequency of c9FTD/ALS was 3.4% (2/58 cases) in FALS. No patients with sporadic ALS (n=110) or control individuals (n=180) had the expansion. Neuropathological findings of an autopsy case were indistinguishable from those of white patients. Although the frequency of risk alleles identified in white subjects is low in Japanese, one patient had all 20 risk alleles and the other had all but one. The estimated haplotype indicated that the repeat expansion in these patients was located on the chromosome with the risk haplotype identified in white subjects. Conclusions C9ORF72 repeat expansions were present in a Japanese cohort of ALS patients, but they were rare. Intriguingly, Japanese patients appear to carry the same risk haplotype identified in white populations.

DOI： 10.1136/jnnp-2012-302272

Scopus

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

A 62-year-old woman had progressive dysarthria for 2 months and was suspected of having amyotrophic lateral sclerosis because of the presentation of bilateral tongue atrophy and fasciculation. Brain magnetic resonance imaging (MRI) showed enlargement of the left hypoglossal nerve, and whole-body gallium scintigraphy showed abnormal uptake in the left pelvic cavity and left thigh. On the basis of the findings of biopsy of the mass lesion in the left thigh, she was diagnosed with diffuse large B-cell lymphoma. After chemotherapy for diffuse large B-cell lymphoma, the tongue atrophy improved. The patient subsequently developed left oculomotor nerve palsy, weakness of the right arm, and weakness of the right leg. The cause of these symptoms was thought to be neurolymphomatosis on the basis of the typical MRI findings observed. We report a rare case of neurolymphomatosis presenting as bilateral tongue atrophy, mimicking amyotrophic lateral sclerosis.

DOI： 10.5692/clinicalneurol.52.589

Scopus

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J01550&link_issn=&doc_id=20120809240010&doc_link_id=10.5692%2Fclinicalneurol.52.589&url=https%3A%2F%2Fdoi.org%2F10.5692%2Fclinicalneurol.52.589&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ROENTGEN RAY SOC  

DOI： 10.2214/AJR.10.4539

Web of Science

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Language：Japanese   Publisher：新潟医学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2009&ichushi_jid=J00990&link_issn=&doc_id=20091124040008&doc_link_id=%2Fdg3nigta%2F2009%2F012307%2F008%2F0373-0373%26dl%3D2&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2009%2F012307%2F008%2F0373-0373%26dl%3D2&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_5.gif

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Societas Neurologica Japonica  

A 75-year-old woman developed loss of vision and decreased ocular motility in all directions. She exhibited a left orbital apex syndrome, accompanied by sphenoiditis and hypertrophic pachymeningitis. Voriconazole treatment was initiated on the basis of clinical suspicion, although use of the serum β-D glucan had negative results and a biopsy was not performed. Five days later, the left eye movements started to improve, and at that time the use of the serum aspergillus galactomannan antigen proved to have positive results. Six months later, the patient was neurologically intact and stable, except for a lack of visual acuity in counting fingers. Earlier prognoses of invasive sino-orbital aspergillosis were dismal, especially when corticosteroid therapy was done before diagnosis. This case suggests the usefulness of antifungal agents during the diagnostic procedure even when localized invasive aspergillosis is not ruled out.

DOI： 10.5692/clinicalneurol.48.746

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(株)ニュー・サイエンス社  

神経変性疾患を特徴づける脳内に異常に蓄積するタンパク質には、RNA結合タンパク質が多く含まれる。RNA結合タンパク質は、タンパク質をコードするmRNAのみならず、mRNA前駆体のイントロン領域や非翻訳領域、さらにはノンコーディングRNAに対しても結合し、広範な細胞内機能を担っている。特定の脳タンパク質が異常に蓄積する神経変性疾患の病態を理解し、これを制御するためには、RNA結合タンパク質とこれと関連するRNA代謝の両面からのアプローチが必要となる。近年、RNA結合タンパク質とその標的RNAの量の不均衡が細胞毒性と関連することを示唆する報告が集まりつつある。RNA結合タンパク質と関連するRNAからなるロバストな細胞内制御機構の背後に潜む脆弱因子を特定し、制御することが、これらの脳疾患の克服につながるものと期待したい。(著者抄録)

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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J-GLOBAL

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Language：Japanese   Publisher：生命科学系学会合同年次大会運営事務局  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

J-GLOBAL

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Language：Japanese   Publisher：新潟医学会  

筋萎縮性側索硬化症(amyotrophic lateral sclerosis:ALS)患者の運動神経細胞およびグリア細胞の細胞質内には、TAR DNA-binding protein 43kDa(TDP-43)陽性の封入体を認める。このTDP-43発現量が、ALS患者で亢進しているとの報告がある。一方、核内蛋白であるTDP-43は自己蛋白量調節機構を有しており、通常の状態ではこの過剰は起こり得ない。著者は、この自己蛋白量調節機構の破綻がTDP-43過剰発現および神経細胞障害を引き起こすとの仮説を立て、この自己蛋白量調節機構の破綻による内在性TDP-43過剰発現モデルを構築し、この仮説を検証することを本研究の目的とした。これまでに著者らは、外来性TDP-43過剰発現細胞の解析により、TDP-43エクソン6内の近位選択的イントロンのスプライシングが発現抑制に重要であることを示してきた。本研究では、この選択的スプライシングをモルフォリノアンチセンス核酸により特異的に抑制し、発現抑制機構を破綻させることにより、内在性TDP-43過剰発現状態を誘導することに成功した。さらに、成体マウス髄腔内へのアンチセンス核酸の投与により、脊髄組織においても内在性TDP-43発現を増加させた。これらの結果は、TDP-43発現抑制機構におけるこの選択的スプライシングの意義を決定づけるとともに、この破綻による内在性TDP-43過剰モデルを細胞およびマウス個体において構築したことを意味する。さらに、この内在性TDP-43過剰発現マウスでは、ALS罹患組織でみられるTDP-43C末断片の増加、さらにアポトーシス促進因子であるBIMの発現増加を認めた。これらより、TDP-43エクソン6内の選択的スプライシング効率の減弱は、内在性TDP-43の過剰発現を導き、神経細胞障害を引き起こすことが示唆された。この内在性TDP-43過剰発現モデルが、ALS病態のさらなる解明と治療法開発に貢献することが期待される。(著者抄録)

CiNii Article

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Other Link： http://hdl.handle.net/10191/44293

Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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J-GLOBAL

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Language：Japanese   Publisher：(株)日本臨床社  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：新潟医学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J00990&link_issn=&doc_id=20131128030021&doc_link_id=%2Fdg3nigta%2F2013%2Fs12706%2F016%2F0334-0334%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2013%2Fs12706%2F016%2F0334-0334%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(有)科学評論社  

症例は80歳女性で、9ヵ月前に視界が万華鏡のようになり頭痛も伴ったため他院を受診し両耳側半盲を指摘され、プレドニゾロン(PSL)内服で視力は回復した。今回PSL内服を中止したところ急速に視力が低下し、更に頭部MRIで視交叉に造影病変が認められたため、精査加療目的に当院紹介となった。入院時、視力は両眼とも光覚なく、対光反射は遅鈍で、血清学的に抗アクアポリン4抗体が陽性であった。また髄液検査でタンパク、IgG index、ミエリン塩基性タンパクの上昇を認め、視覚誘発電位検査では両側とも波形は導出不良であった。頭部MRI FLAIR画像で視交叉に高信号病変を認め、更にT2強調画像で脳脊髄液と同等の高信号、T1強調画像で灰白質と比べて低信号を示し、腫大が認められた。左側脳室体部近傍白質にも小病変を認め、視神経限局型視神経脊髄炎spectrum disorderと診断した。ステロイドパルス療法2コース施行しPSLによる後療法を行ったところ、約1ヵ月半後の頭部MRIで視交叉と左側脳室体部近傍白質の造影病変の消失を認め、新聞の文字の判読は困難なものの、人の顔はわかるようになった。

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：WILEY  

C9ORF72 and the 43 kDa TAR DNA-binding protein (TDP-43) are key molecules in the development of TDP-43 pathology in amyotrophic lateral sclerosis (ALS). The hexanucleotide repeat expansion in C9ORF72 also leads to frontotemporal lobar degeneration, whereas mutation of TARDBP mainly causes ALS, indicating that TDP-43 plays a more fundamental role in the development of ALS. In tissues affected with ALS, TDP-43 is dislocated from the nucleus, forms cytoplasmic inclusions, and is phosphorylated and truncated. Accumulating evidence suggests that the disappearance of TDP-43 from the nucleus precedes inclusion formation, indicating that its disappearance from the nucleus is crucial in the development of TDP-43 pathology. Alterations in the quality and quantity of TDP-43 might result in the disappearance of TDP-43 from the nucleus. Regarding quality, phosphorylation and truncation of TDP-43 is not necessary for its disappearance from the nucleus or for inclusion formation. Although it has been speculated that studies of TDP-43 harboring ALS-associated mutations are useful for understanding the molecular pathogenesis of sporadic ALS, the functional and biochemical differences between mutated and wild-type TDP-43 remain unclear. Regarding quantity, an increased amount of TDP-43 is an attractive hypothesis as it has been shown that increased amounts of TDP-43 are toxic. Moreover, several reports have suggested that increased levels of TDP-43 are found in sporadic ALS as well as in ALS with TDP-43 mutations. However, these findings remain controversial. Increased understanding of the mechanisms responsible for regulating TDP-43 will provide a basis for determining the molecular pathogenesis of ALS.

DOI： 10.1002/ncn3.9

Web of Science

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J-GLOBAL

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

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J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：(有)科学評論社  

53歳男性。運動失調と意識障害を伴った横紋筋融解症がレジオネラ肺炎の顕在化に先行した1例を経験した。発熱、歩行不安定感があり、自宅近くを歩行中ふらついて転倒し、動けなくなり救急搬送された。体温40.3℃、著明な発汗、意識レベルはJCS I-1、立位が不安定で体幹失調を認め、CRP、GOT、GPT、ALP、LDH、γ-GPT、CK、尿中ミオグロビンの高値、低酸素血症を認めた。X線で左下葉に軽度の浸潤影を認めた。横紋筋融解症と診断し、セフトリアキソン点滴静注を開始したが、翌日にはPaO2がさらに低下し、X線上左肺野全体に濃度上昇があり胸水の出現が示唆され、CKのさらなる上昇、不穏や多弁、見当織障害を認めた。レジオネラ尿中迅速抗原検査で陽性所見を得て、抗生剤をメシル酸パズフロキサシンとエリスロマイシンの点滴静注に変更し、呼吸状態、炎症所見、CK値は速やかに改善した。意識障害の回復と運動失調も消失し、入院23日目に独歩退院した。

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