Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1

被引:91
作者
Dong, ZZ
Ferger, B
Paterna, JC
Vogel, D
Furler, S
Osinde, M
Feldon, J
Büeler, H
机构
[1] Univ Zurich, Inst Mol Biol, CH-8057 Zurich, Switzerland
[2] ETH, Swiss Fed Inst Technol, Behav Neurobiol Lab, CH-8603 Schwerzenbach, Switzerland
关键词
D O I
10.1073/pnas.2132992100
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Mutations in the parkin gene are linked to autosomal-recessive juvenile parkinsonism (AR-JP). Parkin functions as a ubiquitin protein ligase in the degradation of several proteins, including the neuron-specific septin CDCrel-1.AR-JP-associated parkin mutations inhibit ubiquitination and degradation of CDCrel-1 and other parkin target proteins. Here we show that recombinant adeno-associated virus-mediated CDCrel-1 gene transfer to the substantial nigra of rats results in a rapid onset (6-10 days) of nigral and striatal CDCrel-1 expression that is followed by a progressive loss of nigral dopaminergic neurons and a decline of the striatal dopamine levels. In contrast, neurons of the globus pallidus are spared from CDCrel-1 toxicity. Furthermore, CDCrel-1 inhibits the release of dopamine from stably-transfected PC12 cells, and pharmacological inhibition of tyrosine hydroxylase and dopamine synthesis in rats prevents CDCrel-1-induced nigral neurodegeneration. These results show that CDCrel-1 overexpression exerts dopamine-dependent neurotoxicity and suggest that inhibition of dopamine secretion by CDCrel-1 may contribute to the development of AR-JP.
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页码:12438 / 12443
页数:6
相关论文
共 57 条
  • [1] A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe
    Abbas, N
    Lücking, CB
    Ricard, S
    Dürr, A
    Bonifati, V
    De Michele, G
    Bouley, S
    Vaughan, JR
    Gasser, T
    Marconi, R
    Broussolle, E
    Brefel-Courbon, C
    Harhangi, BS
    Oostra, AB
    Fabrizio, E
    Böhme, GA
    Pradier, L
    Wood, NW
    Filla, A
    Meco, G
    Denefle, P
    Agid, Y
    Brice, A
    [J]. HUMAN MOLECULAR GENETICS, 1999, 8 (04) : 567 - 574
  • [2] Beites CL, 2001, METHOD ENZYMOL, V329, P499
  • [3] The septin CDCrel-1 binds syntaxin and inhibits exocytosis
    Beites, CL
    Xie, H
    Bowser, R
    Trimble, WS
    [J]. NATURE NEUROSCIENCE, 1999, 2 (05) : 434 - 439
  • [4] Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism
    Bonifati, V
    Rizzu, P
    van Baren, MJ
    Schaap, O
    Breedveld, GJ
    Krieger, E
    Dekker, MCJ
    Squitieri, F
    Ibanez, P
    Joosse, M
    van Dongen, JW
    Vanacore, N
    van Swieten, JC
    Brice, A
    Meco, G
    van Duijn, CM
    Oostra, BA
    Heutink, P
    [J]. SCIENCE, 2003, 299 (5604) : 256 - 259
  • [5] Localization of a novel septin protein, hCDCrel-1, in neurons of human brain
    Caltagarone, J
    Rhodes, J
    Honer, WG
    Bowser, R
    [J]. NEUROREPORT, 1998, 9 (12) : 2907 - 2912
  • [6] The role of the ubiquitin-proteasomal pathway in Parkinson's disease and other neurodegenerative disorders
    Chung, KKK
    Dawson, VL
    Dawson, TM
    [J]. TRENDS IN NEUROSCIENCES, 2001, 24 (11) : S7 - S14
  • [7] Parkin ubiquitinates the α-synuclein-interacting protein, synphilin-1:: implications for Lewy-body formation in Parkinson disease
    Chung, KKK
    Zhang, Y
    Lim, KL
    Tanaka, Y
    Huang, H
    Gao, J
    Ross, CA
    Dawson, VL
    Dawson, TM
    [J]. NATURE MEDICINE, 2001, 7 (10) : 1144 - 1150
  • [8] Kinetic stabilization of the α-synuclein protofibril by a dopamine-α-synuclein adduct
    Conway, KA
    Rochet, JC
    Bieganski, RM
    Lansbury, PT
    [J]. SCIENCE, 2001, 294 (5545) : 1346 - 1349
  • [9] Pathways to parkinsonism
    Cookson, MR
    [J]. NEURON, 2003, 37 (01) : 7 - 10
  • [10] Rare genetic mutations shed light on the pathogenesis of Parkinson disease
    Dawson, TM
    Dawson, VL
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 2003, 111 (02) : 145 - 151