Journal ArticleDOI
Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism
Tohru Kitada,Shuichi Asakawa,Nobutaka Hattori,Hiroto Matsumine,Yasuhiro Yamamura,Shinsei Minoshima,Masayuki Yokochi,Yoshikuni Mizuno,Nobuyoshi Shimizu +8 more
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TLDR
Mutations in the newly identified gene appear to be responsible for the pathogenesis of Autosomal recessive juvenile parkinsonism, and the protein product is named ‘Parkin’.Abstract:
Parkinson's disease is a common neurodegenerative disease with complex clinical features1. Autosomal recessive juvenile parkinsonism (AR-JP)2,3 maps to the long arm of chromosome 6 (6q25.2-q27) and is linked strongly to the markers D6S305 and D6S253 (ref. 4); the former is deleted in one Japanese AR-JP patient5. By positional cloning within this microdeletion, we have now isolated a complementary DNA clone of 2,960 base pairs with a 1,395-base-pair open reading frame, encoding a protein of 465 amino acids with moderate similarity to ubiquitin at the amino terminus and a RING-finger motif at the carboxy terminus. The gene spans more than 500 kilobases and has 12 exons, five of which (exons 3–7) are deleted in the patient. Four other AR-JP patients from three unrelated families have a deletion affecting exon 4 alone. A 4.5-kilobase transcript that is expressed in many human tissues but is abundant in the brain, including the substantia nigra, is shorter in brain tissue from one of the groups of exon-4-deleted patients. Mutations in the newly identified gene appear to be responsible for the pathogenesis of AR-JP, and we have therefore named the protein product ‘Parkin’.read more
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Mutations in NR4A2 associated with familial Parkinson disease.
Weidong Le,Pingyi Xu,Joseph Jankovic,Hong Jiang,Stanley H. Appel,Roy G. Smith,Demetrios K. Vassilatis +6 more
TL;DR: In this paper, two mutations in NR4A2 associated with Parkinson disease (−291Tdel and −245T→G) were identified, which map to the first exon and affect one allele in 10 of 107 individuals with familial Parkinson disease but not in any individuals with sporadic Parkinson disease or in unaffected controls.
Journal ArticleDOI
Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis
Sergio E. Baranzini,Joanne Wang,Rachel A. Gibson,Nicholas Galwey,Yvonne Naegelin,Frederik Barkhof,Ernst Wilhelm Radue,Raija L.P. Lindberg,Bernard Uitdehaag,Marvin Johnson,Marvin Johnson,Aspasia Angelakopoulou,Leslie Hall,Jill C. Richardson,Rab K. Prinjha,Achim Gass,Jeroen J. G. Geurts,J.J. Kragt,Madeleine H. Sombekke,Hugo Vrenken,Pamela Qualley,Robin R. Lincoln,Refujia Gomez,Stacy J. Caillier,Michaela F. George,Hourieh Mousavi,Rosa Guerrero,Darin T. Okuda,Bruce A.C. Cree,Ari J. Green,Emmanuelle Waubant,Douglas S. Goodin,Daniel Pelletier,Paul M. Matthews,Paul M. Matthews,Stephen L. Hauser,Ludwig Kappos,Chris H. Polman,Jorge R. Oksenberg +38 more
TL;DR: Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotype, and independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk.
Journal ArticleDOI
Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease.
Todd L. Edwards,Todd L. Edwards,William K. Scott,Cherylyn Almonte,Amber Burt,Eric Powell,Gary W. Beecham,Liyong Wang,Stephan Züchner,Ioanna Konidari,Gaofeng Wang,Carlos Singer,Fatta B. Nahab,Burton L. Scott,Jeffrey M. Stajich,Margaret A. Pericak-Vance,Jonathan L. Haines,Jeffery M. Vance,Eden R. Martin +18 more
TL;DR: Three independent genome‐wide association studies (GWAS) have investigated the genetic susceptibility to PD and implicated several genes as PD risk loci with strong, but not genome-wide significant, associations.
Journal ArticleDOI
Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD
Kenji Mizumura,Kenji Mizumura,Kenji Mizumura,Suzanne M. Cloonan,Suzanne M. Cloonan,Kiichi Nakahira,Kiichi Nakahira,Abhiram R. Bhashyam,Morgan Cervo,Tohru Kitada,Kimberly Glass,Caroline A. Owen,Ashfaq Mahmood,George R. Washko,Shu Hashimoto,Stefan W. Ryter,Stefan W. Ryter,Augustine M.K. Choi +17 more
TL;DR: It is demonstrated that CS causes mitochondrial dysfunction that is associated with a reduction of mitochondrial membrane potential and implicate mitophagy-dependent necroptosis in lung emphysematous changes in response to CS exposure, suggesting that this pathway is a therapeutic target for COPD.
Journal ArticleDOI
CHIP-Hsc70 Complex Ubiquitinates Phosphorylated Tau and Enhances Cell Survival
TL;DR: It is shown that Alzheimer tau binds to Hsc70, and its phosphorylation is a recognition requirement for the addition of ubiquitin (Ub) by the E3 Ub ligase CHIP and the E2 conjugating enzyme UbcH5B, and therefore the CHIP-Hsc70 complex may provide a new therapeutic target for the tauopathies.
References
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Book
Molecular Cloning: A Laboratory Manual
TL;DR: Molecular Cloning has served as the foundation of technical expertise in labs worldwide for 30 years as mentioned in this paper and has been so popular, or so influential, that no other manual has been more widely used and influential.
Journal ArticleDOI
Mutation in the α-synuclein gene identified in families with Parkinson's disease
Mihael H. Polymeropoulos,Christian Lavedan,Elisabeth Leroy,Susan E. Ide,Anindya Dehejia,Amalia Dutra,Brian L. Pike,Holly Root,Jeffrey Rubenstein,Rebecca Boyer,Edward S. Stenroos,Settara C. Chandrasekharappa,Aglaia Athanassiadou,Theodore Papapetropoulos,William G. Johnson,Alice Lazzarini,Roger C. Duvoisin,Giuseppe Di Iorio,Lawrence I. Golbe,Robert L. Nussbaum +19 more
TL;DR: A mutation was identified in the α-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype.
Journal ArticleDOI
Alpha-synuclein in Lewy bodies.
Maria Grazia Spillantini,Marie L. Schmidt,Virginia M.-Y. Lee,John Q. Trojanowski,Ross Jakes,Michel Goedert +5 more
TL;DR: Strong staining of Lewy bodies from idiopathic Parkinson's disease with antibodies for α-synuclein, a presynaptic protein of unknown function which is mutated in some familial cases of the disease, indicates that the LewY bodies from these two diseases may have identical compositions.
Journal ArticleDOI
Mitochondrial complex I deficiency in Parkinson's disease.
TL;DR: Results indicated a specific defect of Complex I activity in the substantia nigra of patients with Parkinson's disease, which adds further support to the proposition that Parkinson’s disease may be due to an environmental toxin with action(s) similar to those of MPTP.
Journal ArticleDOI
The ubiquitin-proteasome proteolytic pathway
TL;DR: Two studies clearly demonstrate that the ubiquitin-proteasome system is involved not only in complete destruction of its protein substrates, but also in limited proteolysis and posttranslational processing in which biologically active peptides or fragments are generated.
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