Elucidation of pathomechanism of and development of therapy ofautophagy-related muscle disorders

2010 Fiscal Year Final Research Report

• Project/Area Number: 20390250
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: NISHINO Ichizo National Center of Neurology and Psychiatry, ・神経研究所疾病研究第一部, 部長 (00332388)
• Co-Investigator(Kenkyū-buntansha): NOGUCHI Satoru 独立行政法人 国立精神・神経医療研究センター, 神経研究所疾病研究第一部, 室長 (00370982)
• Co-Investigator(Renkei-kenkyūsha): HAYASHI Yukiko 独立行政法人 国立精神・神経医療研究センター, 神経研究所疾病研究第一部, 室長 (50238135) ; NONAKA Ikuya 独立行政法人 国立精神・神経医療研究センター, 病院, 名誉院長 (80040210)
• Research Collaborator: HONDA Shinya 独立行政法人 国立精神・神経医療研究センター, 神経研究所疾病研究第一部, 流動研究員 ; TOMINAGA Kayo 独立行政法人 国立精神・神経医療研究センター, 神経研究所疾病研究第一部, 研究生 ; MONMA Kazunari 独立行政法人 国立精神・神経医療研究センター, 神経研究所疾病研究第一部, 研究生 ; KIYONO Chieko (藤村 智恵子) 独立行政法人 国立精神・神経医療研究センター, 病院, レジデント
• Project Period (FY): 2008 – 2010
• Keywords: 神経分子病態学 / 筋疾患 / オートファジー

Research Abstract

To elucidate the pathomechanism of and to develop the therapy of autophagy-related muscle disorders, we physiologically and pathologically characterized the phenotypes of skeletal and cardiac muscles from Lamp-2 knock-out mice, a model mouse for Danon disease, and analyzed the recovery of phenotype by exogenous expression of the Lamp-2 homolog, Lamp-1. By cross-mating with Lamp-1 overexpressing mouse, cardiac functions was recovered in Lamp-2 knock-out mice. In Lamp-2 deficient cells, degradation by macroautophagy was remarkably decreased. This decrease was corrected by Lamp-1 overexpression. Most likely, Lamp-1 overexpression improves the fusion between autophagosomes and lysosomes, and ameliorates the cell dysfunction caused by Lamp-2 deficiency. Overall, induction of Lamp-1 expression may be a good candidate for the development of therapy for Danon disease.

Research Products

• [Journal Article] Lipid Storage Myopathy (2011)
  • Author(s): Liang WC, Nishino I
  • Journal Title: Curr Neurol Neurosci Rep 11 Pages: 97-103
• [Journal Article] The cathepsin L gene is a direct target of FOXO1 in skeletal muscle (2010)
  • Author(s): Yamazaki Y, Kamei Y, Sugita S, Akaike F, Kanai S, Miura S, Hirata Y, Troen BR, Kitamura T, Nishino I, Suganami T, Ezaki O, Ogawa Y
  • Journal Title: Biochem J 427 Pages: 171-178
  • Peer Reviewed
• [Journal Article] 自己貧食空胞性ミオパチーの病態解明と治療法開発 (2010)
  • Author(s): 西野一三
  • Journal Title: 臨床神経 50 Pages: 1-6
• [Journal Article] 筋疾患とオートファジー (2010)
  • Author(s): 本田真也,西野一三
  • Journal Title: BIO Clinica 25 Pages: 42-46
• [Journal Article] VMA21 deficiency causes an autophagic myopathy by compromising V-ATPase activity and lysosomal acidification (2009)
  • Author(s): Ramachandran N, Munteanu I, Wang P, Aubourg P, Rilstone JJ, Israelian N, Naranian T, Paroutis P, Guo R, Ren ZP, Nishino I, Chabrol B Pellissier JF, Minetti C, Udd B, Fardeau M, Tailor CS, Mahuran DJ, Kissel JT, Kalimo H, Levy N, Manolson MF, Ackerley CA, Minassian BA
  • Journal Title: Cell 137 Pages: 235-246
  • Peer Reviewed
• [Journal Article] Autophagic degradation of nuclear components in mammalian cells (2009)
  • Author(s): Park YE, Hayashi YK, Bonne G, Arimura T, Noguchi S, Nonaka I, Nishino I
  • Journal Title: Autophagy 5 Pages: 795-804
  • Peer Reviewed
• [Journal Article] Congenital myotonic dystrophy can show congenital fiber type disproportion pathology (2009)
  • Author(s): Tominaga, Hayashi YK, Goto K, Minami N, Noguchi S, Nonaka I, Miki T, Nishino I
  • Journal Title: Acta Neuropathol 119 Pages: 481-486
  • Peer Reviewed
• [Journal Article] Danon病患者17家系51例における心筋障害の臨床的特徴 (2009)
  • Author(s): 杉江和馬,埜中征哉,西野一三
  • Journal Title: 心臓 41 Pages: 413-418
• [Journal Article] Pompe病 (2009)
  • Author(s): 門間一成,西野一三
  • Journal Title: Clinical Neuroscience 27 Pages: 370-371
• [Journal Article] Chapter 19 Monitoring Autophagy in Muscle Diseases (2009)
  • Author(s): Malicdan MCV, Noguchi S, Nishino I
  • Journal Title: Methods Enzymol 453C Pages: 379-396
• [Journal Article] Genotype and phenotype analyses in 136 patients with single large-scale mitochondrial DNA deletions (2008)
  • Author(s): Yamashita S, Nishino I, Nonaka I, Goto Y
  • Journal Title: J Hum Genet 53 Pages: 598-606
  • Peer Reviewed
• [Journal Article] Diminished binding of mutated collagen VI to the extracellular matrix surrounding myocytes (2008)
  • Author(s): Kawahara G, Ogawa M, Okada M, Malicdan MCV, Goto Y, Hayashi YK, Noguchi S, Nishino I
  • Journal Title: Muscle Nerve 38 Pages: 1192-1195
  • Peer Reviewed
• [Journal Article] 縁取り空胞を伴う遠位型ミオパチーの治療法開発 (2008)
  • Author(s): 西野一三
  • Journal Title: 医学のあゆみ 226 Pages: 436-440
• [Journal Article] 酵素欠損筋疾患の新しい治療 (2008)
  • Author(s): 門間一成,西野一三
  • Journal Title: メディカルバイオ 5 Pages: 38-43
• [Journal Article] 脂質代謝異常によるミオパチー (2008)
  • Author(s): 門間一成, 梁文貞, 西野一三
  • Journal Title: 医学のあゆみ 226 Pages: 422-427
• [Presentation] Lamp-1 overexpression rescues cardiomyopathy in Lamp-2 deficient cells by correcting cellular lysosomal function (2010)
  • Author(s): Honda S, Noguchi S, Malicdan MCV, Hayashi YK, Saftig P, Nishino I
  • Organizer: 15th International Congress of the World Muscle Society (WMS)
  • Place of Presentation: Kumamoto, Japan
  • Year and Date: 2010-10-13
• [Presentation] Congenital form of X-linked myopathy with excessive autophagy associated with VMA21 mutation (2010)
  • Author(s): Ikeda C, Honda R, Komaki H, Sasaki M, Munteanu I, Ramachandran N, Minassian BA, Tsuburaya R, Hayashi YK, Nishino I
  • Organizer: 15th International Congress of the World Muscle Society (WMS)
  • Place of Presentation: Kumamoto, Japan
  • Year and Date: 2010-10-13
• [Presentation] A case of X-linked myopathy with excessive autophagy : the first case in Japan (2010)
  • Author(s): Kurashige T, Takahashi T, Kondo K, Nakamura T, Yamawaki T, Tsuburaya R, Hayashi YK, Nonaka I, Nishino I, Matsumoto M
  • Organizer: 15th International Congress of the World Muscle Society (WMS)
  • Place of Presentation: Kumamoto, Japan
  • Year and Date: 2010-10-13
• [Presentation] Genetic, clinical, and pathological features of congenital fiber type disproportion in Japan (2010)
  • Author(s): Tominaga K, Hayashi YK, Goto K, Minami N, Noguchi S, Nonaka I, Miki T, Nishino I
  • Organizer: 15th International Congress of the World Muscle Society (WMS)
  • Place of Presentation: Kumamoto, Japan
  • Year and Date: 2010-10-13
• [Presentation] Amphiphysin 2 (BIN1) and triad defects in several forms of centronuclear myopathies (2010)
  • Author(s): Toussaint A, Maurer M, Cowling BS, Hnia K, Mohr M, Oldfors A, Schwab Y, Yis U, Maisonobe T, Stojkovic T, Laugel V, Echaniz-Laguna A, Blot S, Mandel JL, Tiret L, Nishino I, Laporte J
  • Organizer: 15th International Congress of the World Muscle Society (WMS)
  • Place of Presentation: Kumamoto, Japan
  • Year and Date: 2010-10-13
• [Presentation] Recent advance in congenital muscular dystrophy (2010)
  • Author(s): 西野一三
  • Organizer: The 6th Congress of Asian Society for Pediatric Research & 51st Annual Meeting of Taiwan Pediatric Association
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2010-04-17
• [Presentation] Sialic Acid Treatment of Distal Myopathy with Rimmed Vacuoles (DMRV) (2010)
  • Author(s): 西野一三
  • Organizer: The 9th Annual Asian and Oceanian Myology Center (AOMC) Scientific Meeting
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2010-03-26
• [Presentation] LAMP1過剰発見によるダノン病治療への試み (2009)
  • Author(s): 本田真也,野口悟,Malicdan MCV,林由起子,Saftig P,西野一三
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2009-12-12
• [Presentation] 縁取り空胞を伴う遠位型ミオパチーの治療法開発 (2009)
  • Author(s): 西野一三,Malicdan MCV,野口悟
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2009-12-10
• [Presentation] Lamp1 overexpression may rescue cardiomyopathy in Lamp2 deficient mice (2009)
  • Author(s): Honda S, Noguchi S, Malicdan MCV, Hayashi YK, Saftig P, Nishino I
  • Organizer: 14th International Congress of the World Muscle Society (WMS)
  • Place of Presentation: Geneva, Switzerland
  • Year and Date: 2009-09-11
• [Presentation] Congenital myotonic dystrophy in patients diagnosed as congenital fiber type disproportion (2009)
  • Author(s): Tominaga K, Hayashi YK, Goto K, Minami N, Noguchi S, Nonaka I, Nishino I
  • Organizer: 14th International Congress of the World Muscle Society (WMS)
  • Place of Presentation: Geneva, Switzerland
  • Year and Date: 2009-09-11
• [Presentation] Sialic acid metabolites preclude the development of myopathic phenotype in the DMRV/hIBM mouse model (2009)
  • Author(s): Malicdan MCV, Noguchi S, Hayashi YK, Nonaka I, Nishino I
  • Organizer: Congress of the World Muscle Society (WMS)
  • Place of Presentation: Geneva, Switzerland
  • Year and Date: 2009-09-09
• [Presentation] Approach to distal myopathies(遠位型ミオパチーへのアプローチ) (2009)
  • Author(s): 埜中征哉
  • Organizer: アジア・オセアニア筋学センター(AOMC)第8回年次総会
  • Place of Presentation: インド(ムンバイ)
  • Year and Date: 2009-05-23
• [Presentation] Becker型筋ジストロフィーにおける縁取り空胞の出現に関する臨床病理学的検討 (2008)
  • Author(s): 門間一成,野口悟,林由起子,南成祐,元吉和夫,鎌倉恵子,埜中征哉,西野一三
  • Organizer: 第49回日本神経学会総会
  • Place of Presentation: 横浜
  • Year and Date: 20085016
• [Presentation] Cytoplasmic body with acid phosphatase activity-Hallmark of adult-onset Pompe disease on muscle pathology (2008)
  • Author(s): Nishino I, Oya Y, Monma K, Noguchi S, Hayashi YK, Nonaka I
  • Organizer: Congress of the World Muscle Society (WMS), Newcastle Upon Tyne
  • Place of Presentation: United Kingdom
  • Year and Date: 2008-10-01
• [Presentation] Clinico-pathological characteristics of the Becker muscle dystrophy with rimmed vacuole (2008)
  • Author(s): Monma K, Noguchi S, Hayashi YK
  • Organizer: Congress of the World Muscle Society (WMS), Newcastle Upon Tyne
  • Place of Presentation: United Kingdom
  • Year and Date: 2008-10-01
• [Presentation] Congenital myotonic dystrophy and myotubular myopathy may be differentiated by type 2C fibers and peripheral halos (2008)
  • Author(s): Fujimura C, Noguchi S, Minami N, Nonaka I, Hayashi YK, Nishino I
  • Organizer: Congress of the World Muscle Society (WMS), Newcastle Upon Tyne
  • Place of Presentation: United Kingdom
  • Year and Date: 2008-10-01
• [Presentation] Novel ETFDH mutations and normal CoQ10 level in Taiwanese patients with multiple acyl-CoA dehydrogenase deficiency (2008)
  • Author(s): Liang WC, Ohkuma A, Hayashi YK, Lopez LC, Hirano M, Nonaka I, Noguchi S, Jong YJ, Nishino I
  • Organizer: Congress of the World Muscle Society (WMS), Newcastle Upon Tyne
  • Place of Presentation: United Kingdom
  • Year and Date: 2008-09-30
• [Presentation] Marinesco-Sjogren syndrome is the third most common congenital muscular dystrophy in Japan (2008)
  • Author(s): 西野一三
  • Organizer: International Workshop for Congenital Muscular Dystrophy
  • Place of Presentation: Iowa City
  • Year and Date: 2008-07-18
• [Presentation] Ullrich congenital muscular dystrophy due to sarcolemma specific coallgen VI deficiency (2008)
  • Author(s): 西野一三
  • Organizer: International Workshop for Congenital Muscular Dystrophy
  • Place of Presentation: Iowa City
  • Year and Date: 2008-07-17
• [Presentation] Fukuyama congenital muscular dystrophy (2008)
  • Author(s): 西野一三
  • Organizer: International Workshop for Congenital Muscular Dystrophy
  • Place of Presentation: Iowa City
  • Year and Date: 2008-07-17
• [Presentation] RYR1-related core and non-core myopathies (2008)
  • Author(s): 西野一三
  • Organizer: Myology 2008
  • Place of Presentation: Marseille
  • Year and Date: 2008-05-29
• [Presentation] Muatation analysis and response to riboflavin therapy in Taiwanese MADD patients (2008)
  • Author(s): Liang WC, Ohkuma A, Goto K, Hayashi YK, Jong YJ, Nishino I
  • Organizer: 第50回日本小児神経学会総会
  • Place of Presentation: 東京
  • Year and Date: 2008-05-29
• [Presentation] Alpha-dystroglycanopathies in Japan (2008)
  • Author(s): 西野一三
  • Organizer: International Workshop on Muscular Dystrophies
  • Place of Presentation: Charlotte
  • Year and Date: 2008-05-15
• [Book] Muscular Dystrophies. International Encyclopedia Of Public Health, 1st ed. (edited by Quah S, Heggenhougen K) (2008)
  • Author(s): Astejada M, Malicdan MCV, Nishino I
  • Total Pages: 486-496
  • Publisher: Elsevier, Amsterdam, Netherlands