The analysis of Familial Parkinson's disease gene products and the research for identification of a novel Familial Parkinson's disease gene

• Project/Area Number: 17390256
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: JUNTENDO UNIVERSITY
• Principal Investigator: HATTORI Nobutaka Juntendo Medical, Professor, 医学部, 教授 (80218510)
• Co-Investigator(Kenkyū-buntansha): SATO Kenichi Juntendo Medical, Associate Professor, 医学部, 准教授 (00276461) ; KUBO Shin-ichiro Juntendo Medical, Associate Professor, 医学部, 准教授 (20327795) ; HIRASAWA Motoyuki Juntendo Medical, Associate Professor, 医学部, 准教授 (90338393) ; 町田 裕 順天堂大学, 医学部, 助手 (90317470) ; 水野 美邦 順天堂大学, 医学部, 教授 (30049043)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥15,300,000 (Direct Cost: ¥15,300,000); Fiscal Year 2006: ¥7,400,000 (Direct Cost: ¥7,400,000); Fiscal Year 2005: ¥7,900,000 (Direct Cost: ¥7,900,000)
• Keywords: Parkinson's disease / Familial Parkinson's disease / ubiquitin-proteasome / 24-kDa subunit / mitochondrial dysfunction / PINK1 / DJ-1 / Knock-out mice / 24-Daサブユニット / 家族性パーキンソン病 / パーキン / alpha-synuclein / duplication / アグリゾーム / 14-3-3η / ドパミンキノン体 / LRRK2

Research Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder with a prevalence of 1% in individuals older than 65 years of age. Although the majority of PD cases are sporadic, it is now clear that genetic factors contribute to the pathogenesis of PD. Until now, seven causative genes for familial PD (FPD) have been identified. Considering the clinical phenotypes such as parkinsonism, it would be possible that FPD gene products share a common pathway. As parkin is direct linked to ubiquitin-pathway as an E3, this product is also thought to function for mitochondria. PINK1 and DJ-1 are also associated with mitochondria. Thus, mitochondrion is a target organella for elucidating the pathogenesis of FPD. In the present study, we found a common pathway between α-synuclein, parkin, PINK1, and DJ-1. In contrast, half of the autosomal recessive FPD showed no mutations in the known causative genes Therefore, we continue to perform the linkage study for identification of a novel gene. On the mapping for a causative gene responsible for late onset PD with autosomal recessive mode of inheritance, a few loci for this form of PD could be identified.

Research Products

• [Journal Article] Sept4, a Component of Presynaptic Scaffold and Lewy Bodies, Is Required for the Suppression of alpha-Synuclein Neurotoxicity. (2007)
  • Author(s): Ihara M, Yamasaki N, Hagiwara A, Tanigaki A, Kitano A, Hikawa R, Tomimoto H, Noda M, Takanashi M, Mori H, Hattori N, Miyakawa T, Kinoshita M.
  • Journal Title: Neuron 53 Pages: 519-533
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Screening for Lrrk2 G2019S and clinical comparison of Tunisian and North American Caucasian Parkinson's disease families. (2007)
  • Author(s): Ishihara L, Gibson RA, Warren L, Amouri R, Lyons K, Wielinski C, Hunter C, Swartz JE, Elango R, Akkari PA, Leppert D, Surh L, Reeves KH, Thomas S, Ragone L, Hattori N, Pahwa R, Jankovic J, Nance M, Freeman A, Gouider-Khouja N, Kefi M, Zouari M, Ben Sassi S, Ben Yahmed S, El Euch-Fayeche G, Middleton L, Burn DJ, Watts RL, Hentati F
  • Journal Title: Mov Disord 22 Pages: 55-61
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] LRRK2 G2385R variant is a risk factor for Parkinson disease in Asian population (2007)
  • Author(s): Funayama M, Li Y, Tomiyama H, Yoshino H, Imamichi Y, Yamamoto M, Murata M, Toda T, Mizuno Y, Hattori N
  • Journal Title: Neuroreport 18 Pages: 273-275
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Neuropsychiatric and cognitive features in autosomal-recessive early parkinsonism due to PINK1 mutations (2007)
  • Author(s): Ephraty L, Porat O, Israeli D, Cohen OS, Tunkel O, Yael S, Hatano Y, Hattori N, Hassin-Baer S
  • Journal Title: Mov Disord 22 Pages: 566-569
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Dopaminergic neuronal dysfunction associated with parkinsonism in both a Gaucher disease patient and a carrier (2007)
  • Author(s): Kono S, Shirakawa K, Ouchi Y, Sakamoto M, Ida H, Sugiura T, Tomiyama H, Suzuki H, Takahashi Y, Miyajima H, Hattori N, Mizuno Y.
  • Journal Title: J Neurol Sci 252 Pages: 181-184
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Leucine-rich repeat kinase 2 associates with lipid rafts (2007)
  • Author(s): Hatano T, Kubo SI, Imai S, Maeda M, Ishikawa K, Mizuno Y, Hattori N
  • Journal Title: Hum Mol Genet 16 Pages: 678-690
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Parkinson's disease : a hint to elucidate the mechanisms of nigral degeneration. (2007)
  • Author(s): Ihara M, Yamasaki N, Hagiwara A, Tanigaki A, Kitano A, Hikawa R, Tomimoto H, Noda M, Takanashi M, Mori H, Hattori N, Miyakawa T, Kinoshita M, Familial
  • Journal Title: Neuron 53 Pages: 519-533
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Screening for Lrrk2 G2019S and clinical comparison of Tunisian and North American Caucasian Parkinson's disease families (2007)
  • Author(s): Ishihara L, Gibson RA, Warren L, Amouri R, Lyons K, Wielinski C, Hunter C, Swartz JE, Elango R, Akkari PA, Leppert D, Surh L, Reeves KH, Thomas S, Ragone L, Hattori N, Pahwa R, Jankovic J, Nance M, Freeman A, Gouider-Khouja N, Kefi M, Zouari M, Ben Sassi S, Ben Yahmed S, El Euch-Fayeche G, Middleton L, Burn DJ, Watts RL, Hentati F
  • Journal Title: Mov Disord 22 Pages: 55-61
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Decline of striatal dopamine release in parkin-deficient mice shown by ex vivo autoradiography (2007)
  • Author(s): Sato S, Chiba T, Nishiyama S, Kakiuchi T, Tsukada H, Hatano T, Fukuda T, Yasoshima Y, Kai N, Kobayashi K, Mizuno Y, Tanaka K, Hattori N
  • Journal Title: J Neurosci Res 84 Pages: 1350-1357
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Prognosis of Parkinson's disease : time to stage III, IV, V, and to motor fluctuations (2007)
  • Author(s): Sato K, Hatano T, Yamashiro K, Kagohashi M, Nishioka K, Izawa N, Mochizuki H, Hattori N, Mori H, Mizuno Y
  • Journal Title: Mov Disord 21 Pages: 1384-1395
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Dopaminergic neuronal dysfunction associated with parkinsonism in both a Gaucher disease patient and a carrier (2007)
  • Author(s): Kono S, Shirakawa K, Ouchi Y, Sakamoto M, Ida H, Sugiura T, Tomiyama H, Suzuki H, Takahashi Y, Miyajima H, Hattori N, Mizuno Y
  • Journal Title: J Neurol Sci 252 Pages: 181-184
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Screening for Lrrk2 G2019S and clinical comparison of Tunisian and North American Caucasian Parkinson's disease families. (2007)
  • Author(s): Ishihara L, Gibson RA, Warren L, Amouri R, Lyons K, Wielinski C, Hunter C, Swartz JE, Elango R, Akkari PA, Leppert D, Surh L, Reeves KH, Thomas S, Ragone L, Hattori N, Pahwa R, Jankovic J, Nance M, Freeman A, Gouider-Khouja N, Kefi M, Zouari M, Ben Sassi S, Ben Yahmed S, El Euch-Fayeche G, Middleton L, Burn DJ, Watts RL, Hentati F.
  • Journal Title: Mov Disord 22 Pages: 55-61
• [Journal Article] Neuropsychiatric and cognitive features in autosomal-recessive early parkinsonism due to PINK1 mutations (2007)
  • Author(s): Ephraty L, Porat O, Israeli D, Cohen OS, Tunkel O, Yael S, Hatano Y, Hattori N, Hassin-Baer S
  • Journal Title: Mov Disord Jan 26 (Epub ahead of print)
• [Journal Article] Neuropsychiatric and cognitive features in autosomal-recessive early parkinsonism due to PINK1 mutations (2007)
  • Author(s): Hatano T, Kubo SI, Imai S, Maeda M, Ishikawa K, Mizuno Y, Hattori N
  • Journal Title: Hum Mol Genet Mar 6 (epub ahead of print)
• [Journal Article] Prognosis of Parkinson's disease : time to stage III, IV, V, and to motor fluctuations. (2006)
  • Author(s): Sato K, Hatano T, Yamashiro K, Kagohashi M, Nishioka K, Izawa N, Mochizuki H, Hattori N, Mori H, Mizuno Y
  • Journal Title: Mov Disord 21 Pages: 1384-1395
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Decline of striatal dopamine release in parkin-deficient mice shown by ex vivo autoradiography (2006)
  • Author(s): Sato S, Chiba T, Nishiyama S, Kakiuchi T, Tsukada H, Hatano T, Fukuda T, YasoshimaY, Kai N, Kobayashi K, Mizuno Y, Tanaka K, Hattori N
  • Journal Title: J Neurosci Res 84 Pages: 1350-1357
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Nuclear localization of the 20S proteasome subunit in Parkinson's disease (2006)
  • Author(s): Nakamura A, Kitami T, Mori H, Mizuno Y, Hattori N
  • Journal Title: Neurosci Lett 406 Pages: 43-48
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Recessive Parkinson's disease (2006)
  • Author(s): Kubo S, Hattori N, Mizuno Y
  • Journal Title: Mov Disord 21 Pages: 885-893
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Bispecific antibodies against modified protein and DNA with oxidized lipids (2006)
  • Author(s): Akagawa M, Ito S, Toyoda K, Ishii Y, Tatsuda E, Shibata T, Kawai Y, Ishino K, Kishi Y, Adachi T, Tsubata T, Takasaki Y, Hattori N, Matsuda T, Uchida K
  • Journal Title: Proc Natl Acad Sci USA 103 Pages: 6160-6165
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Clinicogenetic study of mutations in LRRK2 exon 41 in Parkinson's disease patients from 18 countries (2006)
  • Author(s): Tomiyama H, Li Y, Funayama M, Hasegawa K, Yoshino H, Kubo S, Sato K, Hattori T, Lu C-S, Inzelberg R, Djaldetti R, Melamed E, Amouri R, Gouider-Khouja N, Hentati F, Hatano Y, Wang M, Imamichi Y, Mizoguchi K, Miyajima H, Obata F, Toda T, Farrer MJ, Mizuno Y, Hattori N
  • Journal Title: Mov Disord 21 Pages: 1102-1108
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 14-3-3 eta is a novel regulator of parkin ubiquitin-ligase (2006)
  • Author(s): Sato S, Chiba T, Sakata E, Kato K, Mizuno Y, Hattori N, Tanaka K
  • Journal Title: EMBO J 25 Pages: 211-221
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Diverse effects of pathogenic mutations of Parkin that catalyzes multiple monoubiquitylation in vitro (2006)
  • Author(s): Matsuda N, Kitami T, Suzuki T, Mizuno Y, Hattori N, Tanaka K
  • Journal Title: J Biol Chem 281 Pages: 3204-3209
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Clinical heterogeneity of alpha-synuclein gene duplication in Parkinson's disease (2006)
  • Author(s): Nishioka K, Hayashi S, Farrer MJ, Singleton AB, Yoshino H, Imai H, Kitami T, Sato K, Kuroda R, Tomiyama H, Mizoguchi K, Murata M, Toda T, Imoto I, Inazawa J, Mizuno Y, Hattori N
  • Journal Title: Ann Neurol 59 Pages: 298-309
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Dominant-negative effect of mutant valosin-containing protein in aggresome formation (2006)
  • Author(s): Kitami MI, Kitami T, Nagahama M, Tagaya M, Hori S, Kakizuka A, Mizuno Y, Hattori N
  • Journal Title: FEBS Lett 580 Pages: 474-478
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Positive immunoreactivity for vesicular monoamine transporter 2 in Lewy bodies and Lewy neurites in substantia nigra (2006)
  • Author(s): Yamamoto S, Fukae J, Mori H, Mizuno Y, Hattori N
  • Journal Title: Neurosci Lett 396 Pages: 187-191
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Multiple candidate gene analysis identifies alpha-synuclein as a susceptibility gene for sporadic Parkinson's disease (2006)
  • Author(s): Mizuta I, Satake W, Nakabayashi Y, Ito C, Suzuki S, Momose Y, Nagai Y, Oka A, Inoko H, Fukae J, Saito Y, Sawabe M, Murayama S, Yamamoto M, Hattori N, Murata M, Toda T
  • Journal Title: Hum Mol Genet 15 Pages: 1151-1158
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Clinical features of Parkinson's patients with and without LRRK2 mutations (2006)
  • Author(s): Ishihara L, Gibson RA, Warren L, Amouri R, Lyons K, Wielinski C, Hunter C, Swartz JE, Elango R, Akkari A, Leppert D, Surh L, Reeves KH, Thomas S, Ragone L, Hattori N, Pahwa R, Jankovic J, Nance M, Freeman A, Gouider-Khouja N, Kefi M, Bouar M, Sassi SB, Yahmed SB, Euch-Fayeche EG, Middleton L, Burn DJ, Watts RL, I Hentati F
  • Journal Title: Arch Neurol 63 Pages: 1250-1254
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease (2006)
  • Author(s): Maraganore DM, de Andrade M, Elbaz A, Farrer MJ, Ioannidis JP, Kruger R, Rocca WA, Schneider NK, Lesnick TG, Lincoln SJ, Hulihan MM, Aasly JO, Ashizawa T, Chartier-Harlin MC, Checkoway H, Ferrarese C, Hadjigeorgiou G, Hattori N, Kawakami H, Lambert JC, Lynch T, Mellick GD, Papapetropoulos S, Parsian A, Quattrone A, Riess O, Tan EK, Van Broeckhoven C
  • Journal Title: JAMA 296 Pages: 661-670
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Recessive Parkinson's disease (2006)
  • Author(s): Kubo S, Hattori N, Mizuno Y
  • Journal Title: Mov Disord. 21 Pages: 885-893
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Positive immunoreactivity for vesicular monoamine transporter 2 in Lewy bodies and Lewy neurites in substantia nigra (2006)
  • Author(s): Yamamoto S, Fukae J, Mori H, Mizuno Y, Hattori N
  • Journal Title: FEBS Lett 580 Pages: 187-191
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Clinical features of Parkinson's patients with and without LRRK2 mutations (2006)
  • Author(s): Ishihara L, Gibson RA, Warren L, Amouri R, Lyons K, Wielinski C, Hunter C, Swartz JE, Elango R, Akkari A, Leppert D, Surh L, Reeves KH, Thomas S, Ragone L, Hattori N, Pahwa R, Jankovic J, Nance M, Freeman A, Gouider-Khouja N, Kefi M, Bouar M, Sassi SB, Yahmed SB, Euch-Fayeche EG, Middleton L, Burn DJ, Watts RL, 1 Hentati F
  • Journal Title: Arch Neurol 63 Pages: 1250-1254
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Van Broeckhoven C, Collaborative analysis of alnha-synuclein gene promoter variability and Parkinson disease (2006)
  • Author(s): Maraganore DM, de Andrade M, Elbaz A, Farrer MJ, Ioannidis JP, Kruger R, Rocca WA, Schneider NK, Lesnick TG, Lincoln SJ, Hulihan MM, Aasly JO, Ashizawa T, Chartier-Harlin MC, Checkoway H, Ferrarese C, Hadjigeorgiou G Hattori N, Kawakami H, Lambert JC, Lynch T, Mellick GD, Papapetropoulos S, Parsian A, Quattrone A, Riess O, Tan EK
  • Journal Title: JAMA 296 Pages: 661-670
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Hassin-Baer S of alpha-synuclein gene duplication in Parkinson's disease, Neuropsychiatric and cognitive features in autosomal-recessive early parkinsonism due to PINK1 mutations (2006)
  • Author(s): Ephraty L, Porat 0, Israeli D, Cohen OS, Tunkel 0, Yael S, Hatano Y, Hattori N
  • Journal Title: Mov Disord 59 Pages: 298-309
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Decline of striatal dopamine release in parkin-deficient mice shown by ex vivo autoradiography (2006)
  • Author(s): Sato S, Chiba T, Nishiyama S, Kakiuchi T, Tsukaba H, Hatano T, Fukuda T, Yasoshima Y, Kai N, Kobayashi K, Mizuno Y, Tanaka K, Hattori N
  • Journal Title: J Neurosci Res 84 Pages: 1350-1357
• [Journal Article] Nuclear localization of the 20S proteasome subunit in Parkinson's disease (2006)
  • Author(s): Nakamura A, Kitami T, Mori H, Mizuno Y, Hattori N
  • Journal Title: Neurosci Lett 406 : 43-48, 2006 406 Pages: 43-48
• [Journal Article] Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease (2006)
  • Author(s): Maraganore DM, de Andrade M, Elbaz A, Farrer MJ, Ioannidis JP, Kruger R, Rocca WA, Schneider NK, Lesnick TG, Lincoin SJ, Hulihan MM, Aasly JO, Ashizawa T, Chartier-Harlin MC, Checkoway H, Ferrarese C, Hadjigeorgiou G, Hattori N, Kawakami H, Lambert JC, Lynch T, Mellick GD, Papapetropoulos S, Parsian A, Quattrone A, Riess O, Tann EK, Van Broeckhoven C
  • Journal Title: JAMA 296 Pages: 661-670
• [Journal Article] Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress. (2005)
  • Author(s): Moore DJ, Hattori N et al.
  • Journal Title: Human Molecular Genetics 14 Pages: 71-84
• [Journal Article] Preserved myocardial [(123)I]metaiodobenzylguanidine uptake in autosomal recessive juvenile parkinsonism : First case report. (2005)
  • Author(s): Suzuki M, Hattori N, et al.
  • Journal Title: Movement Disorders 20 Pages: 634-636
• [Journal Article] Dopaminergic dysfunction in unrelated, asymptomatic carriers of a single parkin mutation. (2005)
  • Author(s): Inzelberg R, Hattori N, et al.
  • Journal Title: Neurology 65 Pages: 1843-1843
• [Journal Article] The LRRK2 I2012T,G2019S, and I2020T mutations are rare in Taiwanese patients with sporadic Parkinson's disease. (2005)
  • Author(s): Lu CS, Hattori N, et al.
  • Journal Title: Parkinsonism and Related Disorders 11 Pages: 521-522
• [Journal Article] Preserved cardiac sympathetic nerve accounts for normal cardiac uptake of MIBG in PARK2. (2005)
  • Author(s): Orimo S, Hattori N, et al.
  • Journal Title: Movement Disorders 20 Pages: 1350-1353
• [Journal Article] Genetic association analyses of PHOX2B and ASCL1 in neuropsychiatric disorders : evidence for association of ASCL1 with Parkinson's disease. (2005)
  • Author(s): Ide M, Hattori N, et al.
  • Journal Title: Human Genetics 117 Pages: 520-527
• [Book] 脳神経疾患病態の分子生物学 (2005)
  • Author(s): 服部 信孝, 柴香保里
  • Total Pages: 191
  • Publisher: 南山堂