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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Journal ArticleDOI
Origin of the Mutations in the parkin Gene in Europe: Exon Rearrangements Are Independent Recurrent Events, whereas Point Mutations May Result from Founder Effects
Magali Periquet,Christoph B. Lücking,J. R. Vaughan,Vincenzo Bonifati,Alexandra Durr,Giuseppe De Michele,Martin W.I.M. Horstink,Matthew J. Farrer,Sergei N. Illarioshkin,Pierre Pollak,Michel Borg,Christine Brefel-Courbon,Patrice Denefle,Giuseppe Meco,Thomas Gasser,Monique M.B. Breteler,Nicholas W. Wood,Yves Agid,Alexis Brice +18 more
TL;DR: The results support the hypothesis that exon rearrangements occurred independently, whereas some point mutations, found in families from different geographic origins, may have been transmitted by a common founder.
Journal ArticleDOI
Neuroprotective and neurorestorative signal transduction mechanisms in brain aging: Modification by genes, diet and behavior
Mark P. Mattson,Mark P. Mattson,Wenzhen Duan,Sic L. Chan,Aiwu Cheng,Norman J. Haughey,Devin S. Gary,Zhihong Guo,Jaewon Lee,Katsutoshi Furukawa +9 more
TL;DR: The recent application of modem methods of molecular and cellular biology to the problem of brain aging is revealing a remarkable capacity within brain cells for adaptation to aging and resistance to disease.
Journal ArticleDOI
In parkinsonian substantia nigra, α-synuclein is modified by acrolein, a lipid-peroxidation product, and accumulates in the dopamine neurons with inhibition of proteasome activity
Masayo Shamoto-Nagai,Wakako Maruyama,Yoshio Hashizume,M. Yoshida,Toshihiko Osawa,P. Riederer,M. Naoi +6 more
TL;DR: It is suggested that ACR may initiate vicious cycle of modification and aggregation of proteins, including αSYN, and impaired proteolysis system, to cause neuronal death in PD.
Journal ArticleDOI
Genetics of Parkinson's disease.
TL;DR: These findings prove that there are several genetically distinct forms of PD that can be caused by mutations in single genes, and the elucidation of the molecular sequence of events leading to nigral degeneration in clearly inherited cases is likely to shed light on the molecular pathogenesis of the common sporadic form of this disorder.
Journal ArticleDOI
Unconventional PINK1 localization to the outer membrane of depolarized mitochondria drives Parkin recruitment.
TL;DR: The molecular basis for PINK1 localization on the OMM of depolarized mitochondria rather than release to the cytosol is poorly understood and the Pink1 localization mechanism is disentangled using deletion mutants and a newly established constitutively active Pinks1 mutant.
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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