研究者詳細 - 小野寺　理

論文 - 小野寺　理

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PSP Rating Scaleによる進行性核上性麻痺の経時的変化に関する検討

瀧川洋史, 池内健, 饗場郁子, 森田光哉, 小野寺理, 下畑享良, 徳田隆彦, 村山繁雄, 長谷川一子, 古和久典, 花島律子, 中島健二, JALPACコンソーシアム

臨床神経学 58 ( Suppl. ) S261 - S261 2018年12月

Clinicopathologic Features of Two Patients With Sporadic Amyotrophic Lateral Sclerosis Who Maintained Communication Ability for Over 30 Years. 査読国際誌

Junko Ito, Tetsuro Shimada, Mari Tada, Hiroshi Shimizu, Masatoshi Wakabayashi, Akio Yokoseki, Osamu Onodera, Hitoshi Takahashi, Akiyoshi Kakita

Journal of neuropathology and experimental neurology 77 ( 11 ) 981 - 986 2018年11月

記述言語：英語

We report the clinicopathologic features of 2 unrelated patients with sporadic amyotrophic lateral sclerosis (SALS) supported by tracheostomy and invasive ventilation (TIV) who were able to maintain communication ability for more than 30 years after disease onset. In both cases, the age at onset was younger than the mean, initially the progression of muscle weakness was consistent with that in the majority of SALS patients, and TIV became necessary several years after disease onset. Thereafter, however, their neurologic deterioration slowed and the patients were able to operate computers by facial movements for several decades. At autopsy, neuronal loss appeared to be confined to the motor neuron system. Furthermore, while Betz cells and lower motor neurons in the spinal anterior horns and hypoglossal nucleus were severely depleted, other pyramidal neurons in the motor cortex, and lower motor neurons in the other brainstem motor nuclei were retained. Neuronal and glial cytoplasmic inclusions immunoreactive for phosphorylated 43-kDa TAR DNA-binding protein (TDP-43) were evident in the CNS, but in extremely small numbers. The present patients may represent a distinct subgroup of patients with SALS who are able to maintain communication ability for an extremely long period, accompanied by very mild TDP-43 pathology.

DOI： 10.1093/jnen/nly082

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Identification and functional characterization of novel mutations including frameshift mutation in exon 4 of CSF1R in patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. 査読国際誌

Takeshi Miura, Naomi Mezaki, Takuya Konno, Akio Iwasaki, Naoyuki Hara, Masatomo Miura, Michitaka Funayama, Yuki Unai, Yuichi Tashiro, Kenji Okita, Takeshi Kihara, Nobuo Ito, Yoichi Kanatsuka, David T Jones, Norikazu Hara, Takanobu Ishiguro, Takayoshi Tokutake, Kensaku Kasuga, Hiroaki Nozaki, Dennis W Dickson, Osamu Onodera, Zbigniew K Wszolek, Takeshi Ikeuchi

Journal of neurology 265 ( 10 ) 2415 - 2424 2018年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is caused by mutations in CSF1R. Pathogenic mutations in exons 12-22 including coding sequence of the tyrosine kinase domain (TKD) of CSF1R were previously identified. We aimed to identify CSF1R mutations in patients who were clinically suspected of having ALSP and to determine the pathogenicity of novel CSF1R variants. METHODS: Sixty-one patients who fulfilled the diagnostic criteria of ALSP were included in this study. Genetic analysis of CSF1R was performed for all the coding exons. The haploinsufficiency of CSF1R was examined for frameshift mutations by RT-PCR. Ligand-dependent autophosphorylation of CSF1R was examined in cells expressing CSF1R mutants. RESULTS: We identified ten variants in CSF1R including two novel frameshift, five novel missense, and two known missense mutations as well as one known missense variant. Eight mutations were located in TKD. One frameshift mutation (p.Pro104LeufsTer8) and one missense variant (p.His362Arg) were located in the extracellular domain. RT-PCR analysis revealed that the frameshift mutation of p.Pro104LeufsTer8 caused nonsense-mediated mRNA decay. Functional assay revealed that none of the mutations within TKD showed autophosphorylation of CSF1R. The p.His362Arg variant located in the extracellular domain showed comparable autophosphorylation of CSF1R to the wild type, suggesting that this variant is not likely pathogenic. CONCLUSIONS: The detection of the CSF1R mutation outside of the region-encoding TKD may extend the genetic spectrum of ALSP with CSF1R mutations. Mutational analysis of all the coding exons of CSF1R should be considered for patients clinically suspected of having ALSP.

DOI： 10.1007/s00415-018-9017-2

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ショウジョウバエモデルによるC9-ALS/FTDの病態解明

上山盛夫, 石黒太郎, Gendron Tania F, 今野卓哉, 小山哲秀, 望月秀樹, 和田圭司, 石川欣也, 小野寺理, 永井義隆

Dementia Japan 32 ( 3 ) 435 - 435 2018年9月

Histopathologic features of an autopsied patient with cerebral small vessel disease and a heterozygous HTRA1 mutation. 査読国際誌

Junko Ito, Hiroaki Nozaki, Yasuko Toyoshima, Takashi Abe, Aki Sato, Hideki Hashidate, Shuichi Igarashi, Osamu Onodera, Hitoshi Takahashi, Akiyoshi Kakita

Neuropathology : official journal of the Japanese Society of Neuropathology 2018年5月

記述言語：英語

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary cerebral small vessel disease (CSVD) caused by homozygous or compound heterozygous mutations of the high temperature requirement A serine peptidase 1 gene (HTRA1). Affected patients suffer from cognitive impairment, recurrent strokes, lumbago and alopecia. Recently, clinical studies have indicated that some patients with heterozygous mutations in HTRA1 may also suffer CSVD. Here, we report the histopathologic features of an autopsied 55-year-old male patient who had shown cognitive impairment and multiple cerebral infarcts, and was found to have a heterozygous missense mutation (p.R302Q) in the HTRA1 gene. Histologically, small vessels in the brain and spinal cord showed intimal proliferation, splitting of the internal elastic lamina, and degeneration of smooth muscle cells in the tunica media. Thus, although less severe, the features were quite similar to those of patients with CARASIL, indicating that patients with heterozygous mutations develop CSVD through underlying pathomechanisms similar to those of CARASIL.

DOI： 10.1111/neup.12473

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Predictors of cognitive impairment in multiple system atrophy. 査読国際誌

Masahiro Hatakeyama, Tomoe Sato, Tetsuya Takahashi, Masato Kanazawa, Osamu Onodera, Masatoyo Nishizawa, Takayoshi Shimohata

Journal of the neurological sciences 388 128 - 132 2018年5月

記述言語：英語

OBJECTIVE: To determine predictors of cognitive impairment and frontal dysfunction in patients with multiple system atrophy (MSA). METHODS: We recruited 59 patients with MSA and determined the predictors of a decline in the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) scores. RESULTS: The MMSE scores negatively correlated with disease duration, Unified MSA Rating Scale (UMSARS) part 1 and 4 scores, and residual urine volume, and positively correlated with the coefficient of variation of electrocardiographic RR intervals. The FAB scores negatively correlated with the UMSARS part 2 score, periventricular hyperintensity grade, and deep white matter hyperintense signal grade. A significant predictor of rapidly progressive cognitive impairment was a high residual urine volume. CONCLUSIONS: Impairment of global cognitive function correlates with the long-term disease duration, global disability due to the disease, and autonomic dysfunction, whereas frontal dysfunction correlates with motor function and degeneration of cerebral white matter.

DOI： 10.1016/j.jns.2018.03.017

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Loss of Motor Neurons Innervating Cervical Muscles in Patients With Multiple System Atrophy and Dropped Head. 査読国際誌

Rie Saito, Mari Tada, Yasuko Toyoshima, Masatoyo Nishizawa, Osamu Onodera, Hitoshi Takahashi, Akiyoshi Kakita

Journal of neuropathology and experimental neurology 77 ( 4 ) 317 - 324 2018年4月

記述言語：英語

We investigated whether loss of motor neurons innervating the neck muscles contributes to dropped head (DH) in multiple system atrophy (MSA). From 75 patients with autopsy-proven MSA, we retrieved 3 who had DH (MSA-DH), and examined the 4th cervical cord segments. Neurons of the medial and lateral nuclear groups (MNG and LNG) innervate the neck and shoulder muscles, respectively. We measured the area of individual neurons in the MNG and LNG, and created an area-frequency histogram. Neurons were classified as large or small based on their area, and their total numbers in the MNG and LNG were counted. In the MNG, the numbers of both total neurons and large neurons were significantly lower in MSA patients than in the controls (214.2 ± 91.4 vs 521.3 ± 74.8, p = 0.0030, and 26.2 ± 9.1 vs 88.0 ± 34.6, p = 0.020, respectively), and were significantly lower in MSA-DH than in MSA-nonDH (139.7 ± 7.6 vs 288.7 ± 74.6, p = 0.048, and 18.0 ± 4.1 vs 34.3 ± 4.1, p = 0.016, respectively). There were no differences in the LNG neuron counts between the MSA-DH and MSA-nonDH groups. Loss of cervical motor neurons may be responsible for DH in MSA.

DOI： 10.1093/jnen/nly007

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Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. 査読国際誌

Ishiura H, Doi K, Mitsui J, Yoshimura J, Matsukawa MK, Fujiyama A, Toyoshima Y, Kakita A, Takahashi H, Suzuki Y, Sugano S, Qu W, Ichikawa K, Yurino H, Higasa K, Shibata S, Mitsue A, Tanaka M, Ichikawa Y, Takahashi Y, Date H, Matsukawa T, Kanda J, Nakamoto FK, Higashihara M, Abe K, Koike R, Sasagawa M, Kuroha Y, Hasegawa N, Kanesawa N, Kondo T, Hitomi T, Tada M, Takano H, Saito Y, Sanpei K, Onodera O, Nishizawa M, Nakamura M, Yasuda T, Sakiyama Y, Otsuka M, Ueki A, Kaida KI, Shimizu J, Hanajima R, Hayashi T, Terao Y, Inomata-Terada S, Hamada M, Shirota Y, Kubota A, Ugawa Y, Koh K, Takiyama Y, Ohsawa-Yoshida N, Ishiura S, Yamasaki R, Tamaoka A, Akiyama H, Otsuki T, Sano A, Ikeda A, Goto J, Morishita S, Tsuji S

Nature genetics 50 ( 4 ) 581 - 590 2018年4月

Frequency and characteristics of the TBK1 gene variants in Japanese patients with sporadic amyotrophic lateral sclerosis. 査読国際誌

Genki Tohnai, Ryoichi Nakamura, Jun Sone, Masahiro Nakatochi, Daichi Yokoi, Masahisa Katsuno, Hazuki Watanabe, Hirohisa Watanabe, Mizuki Ito, Yuanzhe Li, Yuishin Izumi, Mitsuya Morita, Akira Taniguchi, Osamu Kano, Masaya Oda, Satoshi Kuwabara, Koji Abe, Ikuko Aiba, Koichi Okamoto, Kouichi Mizoguchi, Kazuko Hasegawa, Masashi Aoki, Nobutaka Hattori, Osamu Onodera, Hiroya Naruse, Jun Mitsui, Yuji Takahashi, Jun Goto, Hiroyuki Ishiura, Shinichi Morishita, Jun Yoshimura, Koichiro Doi, Shoji Tsuji, Kenji Nakashima, Ryuji Kaji, Naoki Atsuta, Gen Sobue

Neurobiology of aging 64 158.e15-158.e19 - 158.e19 2018年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease, and the etiology of sporadic ALS is generally unknown. The TANK-binding kinase 1 (TBK1) gene was identified as an ALS gene contributing to a predisposition toward ALS. To reveal the frequency and characteristics of variants of the TBK1 gene in sporadic ALS patients in Japan, we analyzed the TBK1 gene by exome sequencing in a large Japanese cohort of 713 sporadic ALS patients and 800 controls. We identified known or potentially toxic rare variants of TBK1 gene in 9 patients (1.26%) with sporadic ALS, including 4 novel missense variants (p.V23I, p.H322R, p.R358C, and p.T478I) and 3 loss-of-function variants (p.R357X, p.P378_I379del, and p.T419_G420del). The odds ratio between sporadic ALS patients and controls was 10.2 (p = 0.008, 95% confidence interval = 1.67-62.47). These findings support the contribution of TBK1 to the etiology of sporadic ALS in Japanese patients.

DOI： 10.1016/j.neurobiolaging.2017.12.005

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Case Report: A patient with spinocerebellar ataxia type 31 and sporadic Creutzfeldt-Jakob disease. 査読国際誌

Natsumi Saito, Tomohiko Ishihara, Kensaku Kasuga, Mana Nishida, Takanobu Ishiguro, Hiroaki Nozaki, Takayoshi Shimohata, Osamu Onodera, Masatoyo Nishizawa

Prion 12 ( 2 ) 147 - 149 2018年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

We report a Japanese patient with spinocerebellar ataxia type 31 (SCA31) and sporadic Creutzfeldt-Jakob disease (sCJD). A 52-year-old man developed progressive cognitive impairment after the appearance of cerebellar symptoms. Brain MR diffusion-weighted imaging (DWI) demonstrated a slowly expanding hyperintense lesion in the cerebral cortex. The patient was finally diagnosed as having both SCA31 and sCJD by identification of genetic mutations and by real-time quaking-induced conversion (RT-QUIC) analysis of the cerebrospinal fluid (CSF), respectively. Here, we report the clinical details of this rare combined case, with particular reference to the association between prion protein and the early onset of SCA31.

DOI： 10.1080/19336896.2018.1436926

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Diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation 査読

T. Konno, K. Yoshida, I. Mizuta, T. Mizuno, T. Kawarai, M. Tada, H. Nozaki, S. I. Ikeda, O. Onodera, Z. K. Wszolek, T. Ikeuchi

European Journal of Neurology 25 ( 1 ) 142 - 147 2018年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Blackwell Publishing Ltd

Background and purpose: To establish and validate diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) due to colony-stimulating factor 1 receptor (CSF1R) mutation. Methods: We developed diagnostic criteria for ALSP based on a recent analysis of the clinical characteristics of ALSP. These criteria provide ‘probable’ and ‘possible’ designations for patients who do not have a genetic diagnosis. To verify its sensitivity and specificity, we retrospectively applied our criteria to 83 ALSP cases who had CSF1R mutations (24 of these were analyzed at our institutions and the others were identified from the literature), 53 cases who had CSF1R mutation-negative leukoencephalopathies and 32 cases who had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with NOTCH3 mutations. Results: Among the CSF1R mutation-positive cases, 50 cases (60%) were diagnosed as ‘probable’ and 32 (39%) were diagnosed as ‘possible,’ leading to a sensitivity of 99% if calculated as a ratio of the combined number of cases who fulfilled ‘probable’ or ‘possible’ to the total number of cases. With regard to specificity, 22 cases (42%) with mutation-negative leukoencephalopathies and 28 (88%) with CADASIL were correctly excluded using these criteria. Conclusions: These diagnostic criteria are very sensitive for diagnosing ALSP with sufficient specificity for differentiation from CADASIL and moderate specificity for other leukoencephalopathies. Our results suggest that these criteria are useful for the clinical diagnosis of ALSP.

DOI： 10.1111/ene.13464

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Operation of a P300-based brain-computer interface in patients with Duchenne muscular dystrophy 査読国際誌

Kota Utsumi, Kouji Takano, Yoji Okahara, Tetsuo Komori, Osamu Onodera, Kenji Kansaku

SCIENTIFIC REPORTS 8 ( 1 ) 1753 - 1753 2018年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

A brain-computer interface (BCI) or brain-machine interface is a technology that enables the control of a computer and other external devices using signals from the brain. This technology has been tested in paralysed patients, such as those with cervical spinal cord injuries or amyotrophic lateral sclerosis, but it has not been tested systematically in Duchenne muscular dystrophy (DMD), which is a severe type of muscular dystrophy due to the loss of dystrophin and is often accompanied by progressive muscle weakness and wasting. Here, we investigated the efficacy of a P300-based BCI for patients with DMD. Eight bedridden patients with DMD and eight age-and gender-matched able-bodied controls were instructed to input hiragana characters. We used a region-based, two-step P300-based BCI with green/blue flicker stimuli. EEG data were recorded, and a linear discriminant analysis distinguished the target from other non-targets. The mean online accuracy of inputted characters (accuracy for the two-step procedure) was 71.6% for patients with DMD and 80.6% for controls, with no significant difference between the patients and controls. The P300-based BCI was operated successfully by individuals with DMD in an advanced stage and these findings suggest that this technology may be beneficial for patients with this disease.

DOI： 10.1038/s41598-018-20125-6

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CARASIL families from India with 3 novel null mutations in the HTRA1 gene. 査読国際誌

Veeramani Preethish-Kumar, Hiroaki Nozaki, Sarbesh Tiwari, Seena Vengalil, Maya Bhat, Chandrajit Prasad, Osamu Onodera, Masahiro Uemura, Seshagiri Doniparthi, Jitender Saini, Saraswati Nashi, Kiran Polavarapu, Atchayaram Nalini

Neurology 89 ( 23 ) 2392 - 2394 2017年12月

Clinical/scientific notes 査読

Neurology 89 ( 23 ) 2392 - 2394 2017年12月

The SMN gene copy number states in Japanese ALS patients

Ishihara T, Toyoda S, Koyama A, Tada M, Atsuta N, Nakamura R, Tohnai G, Sone J, Izumi Y, Kaji R, Morita M, Taniguchi A, Kakita A, Sobue G, Nishizawa M, Onodera O

JOURNAL OF THE NEUROLOGICAL SCIENCES 381 211-211 2017年10月

Apparent diffusion coefficient reduction might be a predictor of poor outcome in patients with posterior reversible encephalopathy syndrome. 査読国際誌

Itaru Ninomiya, Masato Kanazawa, Yasuhisa Akaiwa, Takayoshi Shimohata, Kouichirou Okamoto, Osamu Onodera, Masatoyo Nishizawa

Journal of the neurological sciences 381 1 - 3 2017年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

It is thought that posterior reversible encephalopathy syndrome (PRES) is both clinically and radiologically reversible. However, its reversible nature has been challenged based on reports of permanent neurological impairments. The factors that predict the development of irreversible neurological impairment are still unclear. In the present study, we investigated clinical manifestations, laboratory findings, and neuroradiological images to identify predictors of functional outcomes in PRES. We investigated 23 PRES patients. Apparent diffusion coefficient (ADC) reduction was observed in 4 patients in the poor outcome group, whereas no patients presented ADC reduction in the favourable outcome group (p<0.01). Further studies are warranted to evaluate the association between ADC reduction and functional outcome after PRES.

DOI： 10.1016/j.jns.2017.08.002

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New diagnostic criteria for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy in Japan. 査読国際誌

Ikuko Mizuta, Akiko Watanabe-Hosomi, Takashi Koizumi, Mao Mukai, Ai Hamano, Yasuhiro Tomii, Masaki Kondo, Masanori Nakagawa, Hidekazu Tomimoto, Teruyuki Hirano, Makoto Uchino, Osamu Onodera, Toshiki Mizuno

Journal of the neurological sciences 381 62 - 67 2017年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Definite diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy (CADASIL) is mostly done by identification of NOTCH3 mutations. We aimed to develop criteria for selecting patients suspected for CADASIL to undergo genetic testing. SUBJECTS AND METHODS: All subjects were Japanese. We recruited CADASIL patients genetically diagnosed up until 2011 (n=37, Group 1) or after 2011 (n=65, Group 2), 67 young stroke patients (≤55 years old), and 53 NOTCH3-negative CADASIL-like patients. The members of Japanese research committee for hereditary cerebral small vessel disease discussed and generated the new criteria to maximize positive rate in Group 1 CADASIL patients, followed by validation of sensitivity and specificity. RESULTS: In Group 1 CADASIL patients, the ages at onset excluding migraine were distributed widely (37-74 years old) and bimodal (<55 and >55 years old). Frequencies of an autosomal dominant family history and vascular risk factor(s) were 73 and 65%, respectively. From these findings, the panel considered appropriate cut-off values and weighting for each item. In CADASIL Group 1 versus young stroke controls, the sensitivity and specificity of the new criteria were 97.3% and 80.6%, respectively. However, in CADASIL Group 2 versus NOTCH3-negative controls, the sensitivity and specificity were 96.9% and 7.5%, respectively. Forty mutations of NOTCH3 distributed in exons 2-8, 11, 14, 18, 19, and 21 were identified in this study. Ten mutations were unreported ones. CONCLUSION: We propose the new criteria of high sensitivity, which will help physicians to assess the need for genetic testing.

DOI： 10.1016/j.jns.2017.08.009

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Association between dialysis treatment and cognitive decline: A study from the Project in Sado for Total Health (PROST), Japan 査読

Yumi Watanabe, Kaori Kitamura, Kazutoshi Nakamura, Kazuhiro Sanpei, Minako Wakasugi, Akio Yokoseki, Keiko Kabasawa, Osamu Onodera, Takeshi Ikeuchi, Ryozo Kuwano, Takeshi Momotsu, Ichici Narita, Naoto Endo

GERIATRICS & GERONTOLOGY INTERNATIONAL 17 ( 10 ) 1584 - 1587 2017年10月

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

Aim: Evidence for the association between dialysis treatment and cognitive decline is limited. The present study aimed to determine whether dialysis treatment is associated with cognitive decline in adult outpatients of a general hospital in Japan.Methods: This was a cross-sectional substudy of the Project in Sado for Total Etealth (PROST). Total Etealth PROST targeted adult outpatients of a general hospital in Sado City, Niigata, Japan. Among 753 patients (mean age 68.1 11.6 years) analyzed, 66 received dialysis. Cognitive state was evaluated using the Mini-Mental State Examination, and those with a Mini-Mental State Examination score <24 were considered "cognitively declined." The prevalence of cognitive decline was compared by odds ratios calculated with multiple logistic regression analysis. Variables included in the analyses were dialysis, age, sex and self-reported histories of hypertension, diabetes, stroke and ischemic heart disease.Results: Of the 66 dialysis patients, 24 (36.4%) showed cognitive decline, whereas 172 (25.0%) of 687 non-dialysis patients showed cognitive decline. The age and sex-adjusted odds ratio for cognitive decline in dialysis patients was 2.57 (95% confidence interval 1.43-4.61), relative to non-dialysis patients. The odds ratio remained significant (odds ratio 2.69, 95% confidence interval 1.49-4.88) even after adjusting for all covariates.Conclusion: The prevalence of cognitive decline was high in dialysis patients relative to non-dialysis patients among outpatients of a general hospital in Japan..

DOI： 10.1111/ggi.12937

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Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson's disease 査読

Kahori Shiba-Fukushima, Kei-Ichi Ishikawa, Tsuyoshi Inoshita, Nana Izawa, Masashi Takanashi, Shigeto Sato, Osamu Onodera, Wado Akamatsu, Hideyuki Okano, Yuzuru Imai, Nobutaka Hattori

HUMAN MOLECULAR GENETICS 26 ( 16 ) 3172 - 3185 2017年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OXFORD UNIV PRESS

The ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase Parkin, two gene products associated with young-onset Parkinson's disease (PD), participate in mitochondrial quality control. The phosphorylation of mitochondrial polyUb by PINK1, which is activated in a mitochondrial membrane potential (Delta Psi m)-dependent manner, facilitates the mitochondrial translocation and concomitant enzymatic activation of Parkin, leading to the clearance of phospho-polyUb-tagged mitochondria via mitophagy. Thus, Ub phosphorylation is a key event in PINK1-Parkin-mediated mitophagy. Here, we examined the role of phospho-Ub signaling in the pathogenesis of PD using fly PD models, human brain tissue and dopaminergic neurons derived from induced pluripotent stem cells (iPSCs) containing Parkin or PINK1 mutations, as well as normal controls. We report that phospho-Ub signaling is highly conserved between humans and Drosophila, and that phospho-Ub signaling and the relocation of axonal mitochondria upon Delta Psi m reduction are indeed compromised in human dopaminergic neurons containing Parkin or PINK1 mutations. Moreover, phospho-Ub signaling is prominent in tyrosine hydroxylase-positive neurons compared with tyrosine hydroxylase-negative neurons, suggesting that PINK1-Parkin signaling is more required for dopaminergic neurons. These results shed light on the particular vulnerability of dopaminergic neurons to mitochondrial stress.

DOI： 10.1093/hmg/ddx201

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[Overview of Hereditary Spinocerebellar Ataxias in Japan]. 査読

Masayoshi Tada, Akio Yokoseki, Osamu Onodera

Brain and nerve = Shinkei kenkyu no shinpo 69 ( 8 ) 879 - 890 2017年8月

記述言語：日本語

Hereditary spinocerebellar degenerations (SCD) are a group of neurodegenerative disorders characterized by slowly progressive ataxia associated with non-cerebellar neurological signs and symptoms. In the Japanese population, dominantly inherited SCDs are much more common than recessively inherited or X-linked SCDs. The most common dominantly inherited SCD in Japan, as well as in many other countries, is Machado-Joseph disease, also known as spinocerebellar ataxia type 3 (MJD/SCA3). MJD/SCA3 is frequently accompanied by non-cerebellar symptoms, including progressive external ophthalmoplegia, pyramidal signs, dystonia, rigidity, dysarthria, and distal muscle atrophies. SCA6 and SCA31 represent a pure cerebellar subtype of SCD, occasionally accompanied by non-cerebellar signs. Detailed medical history and neurological examination are important for clinicians to diagnose hereditary SCDs, although genetic testing can help confirm the diagnosis. Despite increasing understanding of the molecular mechanisms underlying these fatal diseases, preventive therapies are currently lacking.

DOI： 10.11477/mf.1416200839

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