Amyotrophic Lateral Sclerosis and TDP-43: Elucidation of molecular neuropathology in terms of spread from its beginning

• Project/Area Number: 26250017
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Niigata University
• Principal Investigator: Takahashi Hitoshi 新潟大学, 脳研究所, 教授 (90206839)
• Co-Investigator(Kenkyū-buntansha): 小野寺 理 新潟大学, 脳研究所, 教授 (20303167) ; 豊島 靖子 新潟大学, 脳研究所, 准教授 (20334675) ; 他田 真理 新潟大学, 脳研究所, 助教 (30646394) ; 清水 宏 新潟大学, 脳研究所, 助教 (40608767)
• Co-Investigator(Renkei-kenkyūsha): KAKITA Akiyoshi 新潟大学, 脳研究所, 教授 (80281012) ; SAKIMURA Kenji 新潟大学, 脳研究所, 教授 (40162325) ; IKEUCHI Takeshi 新潟大学, 脳研究所, 教授 (20372469)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥39,780,000 (Direct Cost: ¥30,600,000、Indirect Cost: ¥9,180,000); Fiscal Year 2016: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2015: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2014: ¥22,100,000 (Direct Cost: ¥17,000,000、Indirect Cost: ¥5,100,000)
• Keywords: 筋萎縮性側索硬化症 / 神経病理学 / 脳神経疾患 / 神経変性疾患 / TDP-43

Outline of Final Research Achievements

We found that TDP-43 regulates the level of-its-own protein by alternative splicing within exon 6. Surprisingly, we found that the proportion of TDP-43 mRNA associated with this autoregulation increases in the spinal cord of ALS patients. It was confirmed that this mutant co-localized with TDP-43 immuno-positive inclusion body in anterior horn cells of ALS patients. This suggested that this abnormal protein may be the beginning of ALS lesion.
We reevaluated the cortical TDP-43 pathology in cases of sporadic ALS, using semi-quantitative estimation of pTDP-43-positive dystrophic neurite in the temporal neocortex,the case were divided into three groups, types 1, 2a and 2b. Type 2b has characteristic clinicopathological features. Considering the patient survaival time and severity of motor neuron loss, each group was regarded as independent subtype, indicating that transition from type 1 to type 2a, or from type 2a to type 2b during the disease course appeared unlikely.

Research Products

• [Journal Article] Familial amyotrophic lateral sclerosis with an I104F mutation in the SOD1 gene: multisystem degeneration with neurofilamentous aggregates and SOD1 inclusions. (2017)
  • Author(s): Jiang H, Shimizu H, Shiga A, Tanaka M, Onodera O, Kakita A, Takahashi H.
  • Journal Title: Neuropathology Volume: 37 Issue: 1 Pages: 69-77
  • DOI: 10.1111/neup.12324
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Heterogeneity of cerebral TDP-43 pathology in sporadic amyotrophic lateral sclerosis: Evidence for clinico-pathologic subtypes. (2016)
  • Author(s): Takeuchi R, Tada M, Shiga A, Toyoshima Y, Konno T, Sato T, Nozaki H, Kato T, Horie M, Shimizu H, Takebayashi H, Onodera O, Nishizawa M, Kakita A, Takahashi H.
  • Journal Title: Acta Neuropathol Commun Volume: 4 Issue: 1 Pages: 61-61
  • DOI: 10.1186/s40478-016-0335-2
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43. (2016)
  • Author(s): Koyama A, Sugai A, Kato T, Ishihara T, Shiga A, Toyoshima Y, Koyama M, Konno T, Hirokawa S, Yokoseki A, Nishizawa M, Kakita A, Takahashi H, Onodera O.
  • Journal Title: Nucleic Acids Res Volume: 44 Issue: 12 Pages: 5820-5836
  • DOI: 10.1093/nar/gkw499
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinicopathological characteristics of patients with amyotrophic lateral sclerosis resulting in a totally locked-in state (communication Stage V). (2016)
  • Author(s): Hayashi K, Mochizuki Y, Takeuchi R, Shimizu T, Nagao M, Watabe K, Arai N, Oyanagi K, Onodera O, Hayashi M, Takahashi H, Kakita A, Isozaki E.
  • Journal Title: Acta Neuropathol Commun Volume: 4 Issue: 1 Pages: 107-107
  • DOI: 10.1186/s40478-016-0379-3
  • NAID: 120007113458
  • Peer Reviewed / Open Access
• [Journal Article] Pathological and Clinical Spectrum of Progressive Supranuclear Palsy: With Special Reference to Astrocytic Tau Pathology. (2016)
  • Author(s): Yokoyama Y, Toyoshima Y, Shiga A, Tada M, Kitamura H, Hasegawa K, Onodera O, Ikeuchi T, Someya T, Nishizawa M, Kakita A, Takahashi H.
  • Journal Title: Brain Pathol. Volume: 26 Issue: 2 Pages: 155-166
  • DOI: 10.1111/bpa.12265
  • Peer Reviewed
• [Journal Article] Zinc transporters ZnT3 and ZnT6 are downregulated in the spinal cords of patients with sporadic amyotrophic lateral sclerosis (2015)
  • Author(s): Kaneko M, Noguchi T, Ikegami S, Sakurai T, Kakita A, Toyoshima Y, Kambe T, Yamada M, Inden M, Hara H, Oyanagi K, Inuzuka T, Takahashi H, Hozumi I.
  • Journal Title: J Neurosci Res Volume: 93(2) Issue: 2 Pages: 370-9
  • DOI: 10.1002/jnr.23491
  • NAID: 120007100194
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] TDP-43 による筋萎縮性側索硬化症 (ALS-TDP43) ─ ALS とは. (2015)
  • Author(s): 高橋 均
  • Journal Title: Clin Neurosci Volume: 33 Pages: 315-318
• [Journal Article] Sortilin-related receptor CNS expressed 2 (SorCS2) is localized to Bunina bodies in amyotrophic lateral sclerosis (2015)
  • Author(s): Mori F, Miki Y, Tanji K, Kakita A, Takahashi H, Utsumi J, Sasaki H, Wakabayashi K.
  • Journal Title: Neurosci Lett Volume: 608 Pages: 6-11
  • DOI: 10.1016/j.neulet.2015.09.030
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Globular Glial Mixed Four Repeat Tau and TDP-43 Proteinopathy with Motor Neuron Disease and Frontotemporal Dementia. (2015)
  • Author(s): Takeuchi R, Toyoshima Y, Tada M, Tanaka H, Shimizu H, Shiga A, Miura T, Aoki K, Aikawa A, Ishizawa S, Ikeuchi T, Nishizawa M, Kakita A, Takahashi H.
  • Journal Title: Brain Pathology Volume: in press Issue: 1 Pages: 82-94
  • DOI: 10.1111/bpa.12262
  • Peer Reviewed
• [Journal Article] Bunina bodies in motor and non-motor neurons revisited: A pathological study of an ALS patient after long-term survival on a respirator. (2014)
  • Author(s): Kimura T, Jiang H, Konno T, Seto M, Iwanaga K, Tsujihata M, Satoh A, Onodera O, Kakita A, Takahashi H.
  • Journal Title: Neuropathology Volume: なし Issue: 4 Pages: 392-397
  • DOI: 10.1111/neup.12105
  • Peer Reviewed / Open Access
• [Journal Article] C9ORF72 repeat-associated non-ATG-translated polypeptides are distributed independently of TDP-43 in a Japanese patient with c9ALS (2014)
  • Author(s): Konno T ほか
  • Journal Title: Neuropathol Appl Neurobiol Volume: 40 Issue: 6 Pages: 783-788
  • DOI: 10.1111/nan.12157
  • Peer Reviewed / Open Access
• [Journal Article] TDP-43 pathology in polyglutamine diseases: with reference to amyotrphic lateral sclerosis (2013)
  • Author(s): YasukoToyoshima and Hitoshi Takahashi
  • Journal Title: Neuropathology Volume: 34 Issue: 1 Pages: 77-82
  • DOI: 10.1111/neup.12053
  • Peer Reviewed
• [Presentation] Cerebral TDP-43 pathology in amyotrophic lateral sclerosis. (2017)
  • Author(s): Takahashi H.
  • Organizer: The 10th Congress of Asia Pacific International Academy of Pathology
  • Place of Presentation: Bali, Indonesia
  • Year and Date: 2017-04-24
  • Int'l Joint Research / Invited
• [Presentation] A trade-off theory for TDP-43 proteinopathya ”robust yet fragile” nature of the autoregulation. (2016)
  • Author(s): Sugai A, Onodera O.
  • Organizer: The 4th Symposium on RNA Metabolism in Neurological Disease
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-11-10
  • Int'l Joint Research
• [Presentation] Analysis of intracellular distribution of TDP-43 mRNA in affected spinal motor neuron with ALS. (2016)
  • Author(s): Kato T, Koyama A, Sugai A, Toyoshima Y, Kakita A, Takahashi H, Nishizawa M, Onodera O.
  • Organizer: Key stone symposium: Common Mechanisms of Neurodegeneration
  • Place of Presentation: Keystone (Colorado), USA
  • Year and Date: 2016-06-12
  • Int'l Joint Research
• [Presentation] The expression of Human endogenous retrovirus-K in the neuronal tissues of Japanese ALS patients. (2016)
  • Author(s): Ishihara T, Koyama A, Kato T, Takeuchi R, Tada M, Kakita A, Onodera O.
  • Organizer: Key stone symposium: Common Mechanisms of Neurodegeneration
  • Place of Presentation: Keystone (Colorado), USA
  • Year and Date: 2016-06-12
  • Int'l Joint Research
• [Presentation] Appearance of unique tau-positive astrocytes in the motor cortex in amyotrophic lateral sclerosis. (2016)
  • Author(s): 竹内亮子, 清水 宏, 他田真理, 豊島靖子, 小野寺 理, 西澤正豊, 高橋 均, 柿田明美.
  • Organizer: 第57回日本神経病理学会
  • Place of Presentation: ホテルニューキャッスル（青森県・弘前市）
  • Year and Date: 2016-06-01
• [Presentation] Neuropathology of amyotrophic lateral sclerosis: discovery of TDP-43 and subsequent development. (2015)
  • Author(s): Takahashi H
  • Organizer: First Annual Conference of Neuropatholgy Society of India
  • Place of Presentation: Hyderabad, India
  • Year and Date: 2015-12-19
  • Invited
• [Presentation] Globular glial mixed four repeat tau and TDP-43 proteinopathy with motor neuron disease and frontotemporal dementia. (2015)
  • Author(s): Takeuchi R, Toyoshima Y, Tada M, Shiga A, Miura T, Aoki K, Ikeuchi T, Nishizawa M, Kakita A, Takahashi H
  • Organizer: 26th International Symposium on ALS/MND
  • Place of Presentation: Orlando, USA
  • Year and Date: 2015-12-11
  • Int'l Joint Research
• [Presentation] 大脳皮質下白質に著名なタウ蓄積を認め, 豊富なTDP-43陽性構造の出現を伴った非典型的CBD. (2015)
  • Author(s): 木村正志, 清水 宏, 豊島靖子, 會田 泉, 米持洋介, 中島 孝, 柿田明美, 高橋 均
  • Organizer: 第56回日本神経病理学会
  • Place of Presentation: 九州大学医学部百年講堂（福岡県・福岡市）
  • Year and Date: 2015-06-05
• [Presentation] TDP-43陽性封入体の出現を認めた家族性ALSの姉妹剖検例. (2015)
  • Author(s): 清水 宏, 田中英智, 松崎紗矢香, 黒羽泰子, 金沢雅人, 小池亮子, 堀川 楊, 小柳清光, 小野寺 理, 西澤正豊, 柿田明美, 高橋 均
  • Organizer: 第56回日本神経病理学会
  • Place of Presentation: 九州大学医学部百年講堂（福岡県・福岡市）
  • Year and Date: 2015-06-05
• [Presentation] Distinct patterns of neuronal and glial TDP-43 inclusions in motor cortex. (2015)
  • Author(s): Takeuchi R, Tada M, Toyohima Y, Shiga A, Sato A, Horie M, Takebayashi H, Onodera O, Nishizawa M, Takahashi H, Kakita A
  • Organizer: 第56回日本神経学会
  • Place of Presentation: 朱鷺メッセ（新潟県・新潟市）
  • Year and Date: 2015-05-25
• [Presentation] Amyotrophic lateral sclerosis: discovery of TDP-43 and subsequent development (2014)
  • Author(s): Takahashi H
  • Organizer: The 3rd Congress of Asian Society of Neuropathology
  • Place of Presentation: Convention Plaza of Seoul University, Seoul, Korea
  • Year and Date: 2014-11-06 – 2014-11-08
  • Invited
• [Presentation] Update in amyotrophic lateral sclerosis (2014)
  • Author(s): Onodera O, Nishizawa M, Takahashi H
  • Organizer: The XVIII International Congress of Neuropathology
  • Place of Presentation: Sheraton Rio Hotel & Resort, Rio de Janeiro, Brazil
  • Year and Date: 2014-09-14 – 2014-09-18
  • Invited
• [Presentation] Analysis of intracellular distribution of TDP-43 mRNA in affected spinal motor neuron with ALS (2014)
  • Author(s): Kato T, Koyama A, Sugai A, Toyoshima Y, Takahashi H, Nishizawa M, Onodera O
  • Organizer: The 37th Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: パシフィコ横浜、横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] 「異常蛋白はシナプスを越えるか」TDP-43 (2014)
  • Author(s): 高橋 均
  • Organizer: 第５５回日本神経病理学会
  • Place of Presentation: 学術総合センター、東京
  • Year and Date: 2014-06-05 – 2014-06-07
  • Invited