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Although several Parkin substrates were identified in vitro, this study demonstrates the accumulation of only one, the aminoacyl-tRNA synthetase cofactor p38 protein, in parkin knockout mice.
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The authors report that following EGF stimulation, Parkin physically interacts with and ubiquitinates Eps15, an adaptor involved in EGFR endocytosis. Parkin-deficient cells exhibit increased EGFR endocytosis and decreased activation of the downstream EGFR target Akt, suggesting that Parkin-mediated ubiquitination of Eps15 inhibits EGFR internalization and thus maintains Akt signaling. This work provides significant mechanistic insight into Parkin function in a non-degradative context.
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Fallon L., Belanger C.M., Corera A.T., Kontogiannea M., Regan-Klapisz E., Moreau F., Voortman J., Haber M., Rouleau G., Thorarinsdottir T., et al. A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K-Akt signalling. Nat Cell Biol 8 (2006) 834-842. The authors report that following EGF stimulation, Parkin physically interacts with and ubiquitinates Eps15, an adaptor involved in EGFR endocytosis. Parkin-deficient cells exhibit increased EGFR endocytosis and decreased activation of the downstream EGFR target Akt, suggesting that Parkin-mediated ubiquitination of Eps15 inhibits EGFR internalization and thus maintains Akt signaling. This work provides significant mechanistic insight into Parkin function in a non-degradative context.
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••] were the first to report the consequences of pink1 loss-of-function in vivo and the genetic interaction between pink1 and parkin. Deletion mutants of pink1 in Drosophila showed mitochondrial morphological defects in the male germline and muscle, stress sensitivity and reduced ATP content. The authors also showed unequivocally that Pink1 localizes predominantly to mitochondria in vivo. pink1 mutant phenotypes were rescued by overexpression of parkin, but overexpression of pink1 did not rescue parkin mutant phenotypes. In addition, human PINK1 rescued fly pink1 mutant phenotypes, establishing the functional conservation between human and fly Pink1.
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••] were the first to report the consequences of pink1 loss-of-function in vivo and the genetic interaction between pink1 and parkin. Deletion mutants of pink1 in Drosophila showed mitochondrial morphological defects in the male germline and muscle, stress sensitivity and reduced ATP content. The authors also showed unequivocally that Pink1 localizes predominantly to mitochondria in vivo. pink1 mutant phenotypes were rescued by overexpression of parkin, but overexpression of pink1 did not rescue parkin mutant phenotypes. In addition, human PINK1 rescued fly pink1 mutant phenotypes, establishing the functional conservation between human and fly Pink1.
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••] were the first to report the consequences of pink1 loss-of-function in vivo and the genetic interaction between pink1 and parkin. The authors demonstrate that pink1 deletion in Drosophila results in mitochondrial morphological defects in the male germline, muscle and dopaminergic neurons, reduced ATP content, reduced mitochondrial DNA and protein content, and mild loss of dopaminergic neurons. The authors also report that pink1 mutant phenotypes can be rescued by overexpression of either the fly Bcl-2 homolog buffy or parkin, whereas overexpression of pink1 does not compensate for parkin loss-of-function.
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••] were the first to report the consequences of pink1 loss-of-function in vivo and the genetic interaction between pink1 and parkin. The authors demonstrate that pink1 deletion in Drosophila results in mitochondrial morphological defects in the male germline, muscle and dopaminergic neurons, reduced ATP content, reduced mitochondrial DNA and protein content, and mild loss of dopaminergic neurons. The authors also report that pink1 mutant phenotypes can be rescued by overexpression of either the fly Bcl-2 homolog buffy or parkin, whereas overexpression of pink1 does not compensate for parkin loss-of-function.
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Corti, O.2
Lucking, C.B.3
Hampe, C.4
Muriel, M.P.5
Abbas, N.6
Gu, W.J.7
Hirsch, E.C.8
Rooney, T.9
Ruberg, M.10
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36
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33644778845
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Parkin enhances mitochondrial biogenesis in proliferating cells
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This paper reports the presence of Parkin within mitochondria. Using immunoelectron microscopy, the authors found that the Parkin protein is associated with mitochondrial cristae in a mammalian neuronal cell line under conditions of proliferation. Moreover, Parkin physically interacted with TFAM, and parkin overexpression enhanced transcription and replication of mitochondrial DNA.
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Kuroda Y., Mitsui T., Kunishige M., Shono M., Akaike M., Azuma H., and Matsumoto T. Parkin enhances mitochondrial biogenesis in proliferating cells. Hum Mol Genet 15 (2006) 883-895. This paper reports the presence of Parkin within mitochondria. Using immunoelectron microscopy, the authors found that the Parkin protein is associated with mitochondrial cristae in a mammalian neuronal cell line under conditions of proliferation. Moreover, Parkin physically interacted with TFAM, and parkin overexpression enhanced transcription and replication of mitochondrial DNA.
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(2006)
Hum Mol Genet
, vol.15
, pp. 883-895
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Kuroda, Y.1
Mitsui, T.2
Kunishige, M.3
Shono, M.4
Akaike, M.5
Azuma, H.6
Matsumoto, T.7
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38
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33744963796
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Parkin protects against mitochondrial toxins and beta-amyloid accumulation in skeletal muscle cells
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Rosen K.M., Veereshwarayya V., Moussa C.E., Fu Q., Goldberg M.S., Schlossmacher M.G., Shen J., and Querfurth H.W. Parkin protects against mitochondrial toxins and beta-amyloid accumulation in skeletal muscle cells. J Biol Chem 281 (2006) 12809-12816
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(2006)
J Biol Chem
, vol.281
, pp. 12809-12816
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Rosen, K.M.1
Veereshwarayya, V.2
Moussa, C.E.3
Fu, Q.4
Goldberg, M.S.5
Schlossmacher, M.G.6
Shen, J.7
Querfurth, H.W.8
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39
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30044434872
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Similar patterns of mitochondrial vulnerability and rescue induced by genetic modification of α-synuclein, parkin, and DJ-1 in Caenorhabditis elegans
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Ved R., Saha S., Westlund B., Perier C., Burnam L., Sluder A., Hoener M., Rodrigues C.M.P., Alfonso A., Steer C., et al. Similar patterns of mitochondrial vulnerability and rescue induced by genetic modification of α-synuclein, parkin, and DJ-1 in Caenorhabditis elegans. J Biol Chem 280 (2005) 42655-42668
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(2005)
J Biol Chem
, vol.280
, pp. 42655-42668
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Ved, R.1
Saha, S.2
Westlund, B.3
Perier, C.4
Burnam, L.5
Sluder, A.6
Hoener, M.7
Rodrigues, C.M.P.8
Alfonso, A.9
Steer, C.10
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40
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33747179913
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Parkin affects mitochondrial function and apoptosis in neuronal and myogenic cells
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Kuroda Y., Mitsui T., Kunishige M., and Matsumoto T. Parkin affects mitochondrial function and apoptosis in neuronal and myogenic cells. Biochem Biophys Res Commun 348 (2006) 787-793
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(2006)
Biochem Biophys Res Commun
, vol.348
, pp. 787-793
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Kuroda, Y.1
Mitsui, T.2
Kunishige, M.3
Matsumoto, T.4
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41
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33745274726
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Mitochondria: dynamic organelles in disease, aging, and development
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Chan D.C. Mitochondria: dynamic organelles in disease, aging, and development. Cell 125 (2006) 1241-1252
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(2006)
Cell
, vol.125
, pp. 1241-1252
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Chan, D.C.1
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42
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33750459730
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Parkinsonism genes: culprits and clues
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Abeliovich A., and Flint Beal M. Parkinsonism genes: culprits and clues. J Neurochem 99 (2006) 1062-1072
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(2006)
J Neurochem
, vol.99
, pp. 1062-1072
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Abeliovich, A.1
Flint Beal, M.2
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43
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24044472010
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Drosophila DJ-1 mutants are selectively sensitive to environmental toxins associated with Parkinson's disease
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Meulener M., Whitworth A.J., Armstrong-Gold C.E., Rizzu P., Heutink P., Wes P.D., Pallanck L.J., and Bonini N.M. Drosophila DJ-1 mutants are selectively sensitive to environmental toxins associated with Parkinson's disease. Curr Biol 15 (2005) 1572-1577
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(2005)
Curr Biol
, vol.15
, pp. 1572-1577
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Meulener, M.1
Whitworth, A.J.2
Armstrong-Gold, C.E.3
Rizzu, P.4
Heutink, P.5
Wes, P.D.6
Pallanck, L.J.7
Bonini, N.M.8
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44
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1842740232
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Cysteine-106 of DJ-1 is the most sensitive cysteine residue to hydrogen peroxide-mediated oxidation in vivo in human umbilical vein endothelial cells
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Kinumi T., Kimata J., Taira T., Ariga H., and Niki E. Cysteine-106 of DJ-1 is the most sensitive cysteine residue to hydrogen peroxide-mediated oxidation in vivo in human umbilical vein endothelial cells. Biochem Biophys Res Commun 317 (2004) 722-728
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(2004)
Biochem Biophys Res Commun
, vol.317
, pp. 722-728
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Kinumi, T.1
Kimata, J.2
Taira, T.3
Ariga, H.4
Niki, E.5
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45
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2942684871
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The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization
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Canet-Aviles R.M., Wilson M.A., Miller D.W., Ahmad R., McLendon C., Bandyopadhyay S., Baptista M.J., Ringe D., Petsko G.A., and Cookson M.R. The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci USA 101 (2004) 9103-9108
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(2004)
Proc Natl Acad Sci USA
, vol.101
, pp. 9103-9108
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Canet-Aviles, R.M.1
Wilson, M.A.2
Miller, D.W.3
Ahmad, R.4
McLendon, C.5
Bandyopadhyay, S.6
Baptista, M.J.7
Ringe, D.8
Petsko, G.A.9
Cookson, M.R.10
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46
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33747611218
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Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging
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The authors demonstrate that mutating a conserved cysteine residue in fly DJ-1 to prevent oxidative modification abrogates the ability of DJ-1 to protect against oxidative insults in Drosophila. Mutation of this same residue to aspartic acid to mimic cysteine modification also attenuates the protective action of DJ-1. The authors further report that cysteine modification of DJ-1 increases with age in flies, mice and humans. In flies, increased modification of DJ-1 correlated with reduced oxidative stress tolerance suggesting that, although cysteine modification is required for the protective effects of DJ-1, excessive cysteine modification might counteract this effect.
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Meulener M.C., Xu K., Thomson L., Ischiropoulos H., and Bonini N.M. Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging. Proc Natl Acad Sci USA 103 (2006) 12517-12522. The authors demonstrate that mutating a conserved cysteine residue in fly DJ-1 to prevent oxidative modification abrogates the ability of DJ-1 to protect against oxidative insults in Drosophila. Mutation of this same residue to aspartic acid to mimic cysteine modification also attenuates the protective action of DJ-1. The authors further report that cysteine modification of DJ-1 increases with age in flies, mice and humans. In flies, increased modification of DJ-1 correlated with reduced oxidative stress tolerance suggesting that, although cysteine modification is required for the protective effects of DJ-1, excessive cysteine modification might counteract this effect.
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(2006)
Proc Natl Acad Sci USA
, vol.103
, pp. 12517-12522
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Meulener, M.C.1
Xu, K.2
Thomson, L.3
Ischiropoulos, H.4
Bonini, N.M.5
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47
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24944534660
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Mitochondrial localization of the Parkinson's disease related protein DJ-1: implications for pathogenesis
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Zhang L., Shimoji M., Thomas B., Moore D.J., Yu S.W., Marupudi N.I., Torp R., Torgner I.A., Ottersen O.P., Dawson T.M., et al. Mitochondrial localization of the Parkinson's disease related protein DJ-1: implications for pathogenesis. Hum Mol Genet 14 (2005) 2063-2073
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(2005)
Hum Mol Genet
, vol.14
, pp. 2063-2073
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Zhang, L.1
Shimoji, M.2
Thomas, B.3
Moore, D.J.4
Yu, S.W.5
Marupudi, N.I.6
Torp, R.7
Torgner, I.A.8
Ottersen, O.P.9
Dawson, T.M.10
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48
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33744760852
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Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease
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Tang B., Xiong H., Sun P., Zhang Y., Wang D., Hu Z., Zhu Z., Ma H., Pan Q., Xia J.H., et al. Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease. Hum Mol Genet 15 (2006) 1816-1825
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(2006)
Hum Mol Genet
, vol.15
, pp. 1816-1825
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Tang, B.1
Xiong, H.2
Sun, P.3
Zhang, Y.4
Wang, D.5
Hu, Z.6
Zhu, Z.7
Ma, H.8
Pan, Q.9
Xia, J.H.10
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49
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12344251678
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Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress
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Moore D.J., Zhang L., Troncoso J., Lee M.K., Hattori N., Mizuno Y., Dawson T.M., and Dawson V.L. Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress. Hum Mol Genet 14 (2005) 71-84
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(2005)
Hum Mol Genet
, vol.14
, pp. 71-84
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Moore, D.J.1
Zhang, L.2
Troncoso, J.3
Lee, M.K.4
Hattori, N.5
Mizuno, Y.6
Dawson, T.M.7
Dawson, V.L.8
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50
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30644471051
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Parkinson's disease α-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death
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This study reports that expressing pathogenic mutant forms of SNCA alone in mice results in the presence of aberrant mitochondria in axons and dendrites of affected neurons, reduced activity of the mitochondrial respiratory chain, and mtDNA damage.
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Martin L.J., Pan Y., Price A.C., Sterling W., Copeland N.G., Jenkins N.A., Price D.L., and Lee M.K. Parkinson's disease α-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J Neurosci 26 (2006) 41-50. This study reports that expressing pathogenic mutant forms of SNCA alone in mice results in the presence of aberrant mitochondria in axons and dendrites of affected neurons, reduced activity of the mitochondrial respiratory chain, and mtDNA damage.
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(2006)
J Neurosci
, vol.26
, pp. 41-50
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Martin, L.J.1
Pan, Y.2
Price, A.C.3
Sterling, W.4
Copeland, N.G.5
Jenkins, N.A.6
Price, D.L.7
Lee, M.K.8
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51
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33644543761
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Expanding insights of mitochondrial dysfunction in Parkinson's disease
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Abou-Sleiman P.M., Muqit M.M., and Wood N.W. Expanding insights of mitochondrial dysfunction in Parkinson's disease. Nat Rev Neurosci 7 (2006) 207-219
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(2006)
Nat Rev Neurosci
, vol.7
, pp. 207-219
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Abou-Sleiman, P.M.1
Muqit, M.M.2
Wood, N.W.3
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52
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20044385568
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Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein
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Fornai F., Schluter O.M., Lenzi P., Gesi M., Ruffoli R., Ferrucci M., Lazzeri G., Busceti C.L., Pontarelli F., Battaglia G., et al. Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein. Proc Natl Acad Sci USA 102 (2005) 3413-3418
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(2005)
Proc Natl Acad Sci USA
, vol.102
, pp. 3413-3418
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Fornai, F.1
Schluter, O.M.2
Lenzi, P.3
Gesi, M.4
Ruffoli, R.5
Ferrucci, M.6
Lazzeri, G.7
Busceti, C.L.8
Pontarelli, F.9
Battaglia, G.10
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53
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33745612296
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Intersecting pathways to neurodegeneration in Parkinson's disease: effects of the pesticide rotenone on DJ-1, alpha-synuclein, and the ubiquitin-proteasome system
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Betarbet R., Canet-Aviles R.M., Sherer T.B., Mastroberardino P.G., McLendon C., Kim J.H., Lund S., Na H.M., Taylor G., Bence N.F., et al. Intersecting pathways to neurodegeneration in Parkinson's disease: effects of the pesticide rotenone on DJ-1, alpha-synuclein, and the ubiquitin-proteasome system. Neurobiol Dis 22 (2006) 404-420
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(2006)
Neurobiol Dis
, vol.22
, pp. 404-420
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Betarbet, R.1
Canet-Aviles, R.M.2
Sherer, T.B.3
Mastroberardino, P.G.4
McLendon, C.5
Kim, J.H.6
Lund, S.7
Na, H.M.8
Taylor, G.9
Bence, N.F.10
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54
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34249946941
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Mono- and double-mutant mouse models of Parkinson's disease display severe mitochondrial damage
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10.1093/hmg/ddm083. The authors demonstrate that mitochondria from parkin knockout mice and mice expressing mutant human SNCA exhibit defects in mitochondrial respiration. parkin mutant mice expressing SNCA also displayed age-dependent defects in mitochondrial morphology within dopaminergic neurons. These defects were also seen in mice either mutant for parkin or expressing SNCA more frequently than in wild type mice, but the number of damaged mitochondria only reached statistical significance in mice with both genetic modifications.
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Stichel C.C., Zhu X.R., Bader V., Linnartz B., Schmidt S., and Lubbert H. Mono- and double-mutant mouse models of Parkinson's disease display severe mitochondrial damage. Hum Mol Genet (2007). http://hmg.oxfordjournals.org/ 10.1093/hmg/ddm083. The authors demonstrate that mitochondria from parkin knockout mice and mice expressing mutant human SNCA exhibit defects in mitochondrial respiration. parkin mutant mice expressing SNCA also displayed age-dependent defects in mitochondrial morphology within dopaminergic neurons. These defects were also seen in mice either mutant for parkin or expressing SNCA more frequently than in wild type mice, but the number of damaged mitochondria only reached statistical significance in mice with both genetic modifications.
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(2007)
Hum Mol Genet
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Stichel, C.C.1
Zhu, X.R.2
Bader, V.3
Linnartz, B.4
Schmidt, S.5
Lubbert, H.6
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