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Originally published in Science Express on 15 April 2004
Science 21 May 2004:
Vol. 304. no. 5674, pp. 1158 - 1160
DOI: 10.1126/science.1096284
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Reports

Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1

Enza Maria Valente,1*{ddagger} Patrick M. Abou-Sleiman,2* Viviana Caputo,1,3{dagger} Miratul M. K. Muqit,2,4{dagger} Kirsten Harvey,5 Suzana Gispert,6 Zeeshan Ali,6 Domenico Del Turco,7 Anna Rita Bentivoglio,9 Daniel G Healy,2 Alberto Albanese,10 Robert Nussbaum,11 Rafael González-Maldonado,12 Thomas Deller,7 Sergio Salvi,1 Pietro Cortelli,13 William P. Gilks,2 David S. Latchman,4,14 Robert J. Harvey,5 Bruno Dallapiccola,1,3 Georg Auburger,8{ddagger} Nicholas W. Wood2{ddagger}

Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6). Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6. We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid. Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress. These data provide a direct molecular link between mitochondria and the pathogenesis of PD.

1 CSS IRCCS, Mendel Institute, viale Regina Margherita 261, 00198 Rome, Italy.
2 Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
3 Department of Experimental Medicine and Pathology, University La Sapienza, Viale Regina Elena 324, 00187 Rome, Italy.
4 Medical Molecular Biology Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
5 Department of Pharmacology, The School of Pharmacy, 29/39 Brunswick Square, London WC1N 1AX, UK.
6 Institute for Experimental Neurobiology, J.W. Goethe University, Theodor Stern Kai 7, 60590 Frankfurt/M, Germany.
7 Institute of Clinical Neuroanatomy, J.W. Goethe University, Theodor Stern Kai 7, 60590 Frankfurt/M, Germany.
8 Section of Molecular Neurogenetics, Clinic for Neurology; J.W. Goethe University, Theodor Stern Kai 7, 60590 Frankfurt/M, Germany.
9 Institute of Neurology, Catholic University, largo A. Gemelli 8, I-00168 Rome, Italy.
10 National Neurologic Institute Carlo Besta, via Celoria 11, 20133 Milan, Italy.
11 National Human Genetics Research Institute, National Institutes of Health, 49 Convent Drive, Bethesda, MD 20892, USA.
12 Department of Neurology, Hospital Universitatio San Cecilio, Avenida Dr. Olóriz s/n, 18012 Granada, Spain.
13 Department of Neurosciences, University of Modena and Reggio Emilia, via del Pozzo 71, 41100 Modena, Italy.
14 Birkbeck, University of London, Malet Street, London WC1E 7HX, UK.



* These authors contributed equally to this work.

{dagger} These authors share joint second authorship.

{ddagger} To whom correspondence should be addressed. E-mail: n.wood{at}ion.ucl.ac.uk (N.W.W.); auburger{at}em.uni-frankfurt.de (G.A.); e.valente{at}css-mendel.it (E.M.V.)

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Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit?.
K. Hedrich, J. Hagenah, A. Djarmati, A. Hiller, T. Lohnau, K. Lasek, A. Grunewald, R. Hilker, S. Steinlechner, H. Boston, et al. (2006)
Arch Neurol 63, 833-838
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Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease.
B. Tang, H. Xiong, P. Sun, Y. Zhang, D. Wang, Z. Hu, Z. Zhu, H. Ma, Q. Pan, J.-h. Xia, et al. (2006)
Hum. Mol. Genet. 15, 1816-1825
   Abstract »    Full Text »    PDF »
Etiology of Parkinson's disease.
A. H.V. Schapira (2006)
Neurology 66, S10-S23
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Direct evidence for coherent low velocity axonal transport of mitochondria.
K. E. Miller and M. P. Sheetz (2006)
J. Cell Biol. 173, 373-381
   Abstract »    Full Text »    PDF »
Mitochondria in Parkinson disease: back in fashion with a little help from genetics..
M. M. K. Muqit, S. Gandhi, and N. W. Wood (2006)
Arch Neurol 63, 649-654
   Abstract »    Full Text »    PDF »
Reactive Oxygen Species-Mediated Mitochondria-to-Nucleus Signaling: A Key to Aging and Radical-Caused Diseases.
P. Storz (2006)
Sci. STKE 2006, re3
   Abstract »    Full Text »    PDF »
Multiple candidate gene analysis identifies {alpha}-synuclein as a susceptibility gene for sporadic Parkinson's disease.
I. Mizuta, W. Satake, Y. Nakabayashi, C. Ito, S. Suzuki, Y. Momose, Y. Nagai, A. Oka, H. Inoko, J. Fukae, et al. (2006)
Hum. Mol. Genet. 15, 1151-1158
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Case-control study of the parkin gene in early-onset Parkinson disease..
L. N. Clark, S. Afridi, E. Karlins, Y. Wang, H. Mejia-Santana, J. Harris, E. D. Louis, L. J. Cote, H. Andrews, S. Fahn, et al. (2006)
Arch Neurol 63, 548-552
   Abstract »    Full Text »    PDF »
A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease.
The NINDS NET-PD Investigators (2006)
Neurology 66, 664-671
   Abstract »    Full Text »    PDF »
Implications of genetics on the diagnosis and care of patients with Parkinson disease..
C. Klein (2006)
Arch Neurol 63, 328-334
   Abstract »    Full Text »    PDF »
Mutational analysis of the PINK1 gene in early-onset parkinsonism in Europe and North Africa.
P. Ibanez, S. Lesage, E. Lohmann, S. Thobois, G. D. Michele, M. Borg, Y. Agid, A. Durr, A. Brice, and and the French Parkinson's Disease Genetics Study (2006)
Brain 129, 686-694
   Abstract »    Full Text »    PDF »
Mitochondrial Reactive Oxygen Species in Mice Lacking Superoxide Dismutase 2: ATTENUATION VIA ANTIOXIDANT TREATMENT.
K. J. Morten, B. A. C. Ackrell, and S. Melov (2006)
J. Biol. Chem. 281, 3354-3359
   Abstract »    Full Text »    PDF »
Parkin Ubiquitinates and Promotes the Degradation of RanBP2.
J. W. Um, D. S. Min, H. Rhim, J. Kim, S. R. Paik, and K. C. Chung (2006)
J. Biol. Chem. 281, 3595-3603
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Heterogeneous Phenotype in a Family With Compound Heterozygous Parkin Gene Mutations.
H. Deng, W.-D. Le, C. B. Hunter, W. G. Ondo, Y. Guo, W.-J. Xie, and J. Jankovic (2006)
Arch Neurol 63, 273-277
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The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity.
C. J. Gloeckner, N. Kinkl, A. Schumacher, R. J. Braun, E. O'Neill, T. Meitinger, W. Kolch, H. Prokisch, and M. Ueffing (2006)
Hum. Mol. Genet. 15, 223-232
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Similar Patterns of Mitochondrial Vulnerability and Rescue Induced by Genetic Modification of {alpha}-Synuclein, Parkin, and DJ-1 in Caenorhabditis elegans.
R. Ved, S. Saha, B. Westlund, C. Perier, L. Burnam, A. Sluder, M. Hoener, C. M. P. Rodrigues, A. Alfonso, C. Steer, et al. (2005)
J. Biol. Chem. 280, 42655-42668
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Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism.
L. Silvestri, V. Caputo, E. Bellacchio, L. Atorino, B. Dallapiccola, E. M. Valente, and G. Casari (2005)
Hum. Mol. Genet. 14, 3477-3492
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From The Cover: Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity.
A. B. West, D. J. Moore, S. Biskup, A. Bugayenko, W. W. Smith, C. A. Ross, V. L. Dawson, and T. M. Dawson (2005)
PNAS 102, 16842-16847
   Abstract »    Full Text »    PDF »


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