Nigrostriatal Dopaminergic Deficits and Hypokinesia Caused by Inactivation of the Familial Parkinsonism-Linked Gene DJ-1

Goldberg, Matthew S.; Pisani, Antonio; Haburčák, Marián; Vortherms, Timothy A.; Kitada, Tohru; Costa, Cinzia; Tong, Yiwei; Martella, Giuseppina; Tscherter, Anne; Martins, Andreá Maria Eleutério de Barros Lima; Bernardi, Giorgio; Roth, Bryan L.; Pothos, Emmanuel N.; Calabresi, Paolo; Shen, Jie

doi:10.1016/j.neuron.2005.01.041

Cited by 491 publications

(386 citation statements)

References 26 publications

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“…Prior studies have shown that these inhibitory effects of quinpirole are abolished in mice lacking all D2 receptors, but are retained in mice expressing only the short isoform, which serves presynaptic autoreceptor functions (32,38,39). Interestingly, similar compromises of D2 autoreceptor-mediated functions have been reported in another PD mouse model, DJ-1 Ϫ/Ϫ mice, which also exhibited reduced responses in locomotor activity to quinpirole and reduced responses of nigral neurons to dopamine and quinpirole (26). These results raise the possibility that the D2 autoreceptor-mediated function may be a converging common target of PD mutations, a notion supported by the clinical efficacy of D2 receptor agonists in PD (40).…”

Section: Discussionmentioning

confidence: 65%

“…Immunohistochemical analysis and stereological DA neuron counting, as well as intracellular recordings of nigral neurons, were performed as previously described (26). For immunohistochemical analysis, coronal brain sections were stained with antibodies to TH (Chemicon), total ␣-synuclein (4D6; Abcam) or phosphorylated at Ser-129 (Wako), ubiquitin (Abcam), total tau or phosphorylated tau at Ser-396/404 (PHF-1) or at Ser-202 (CP13) (both were provided by Peter Davies), and glial fibrillary acidic protein (GFAP; Sigma).…”

Section: Methodsmentioning

confidence: 99%

“…We further evaluated dopamine D2 receptor function or signaling in LRRK2 KI/KI mice, which is impaired in DJ-1 KO mice (26), and is involved in feedback regulation of dopamine release (27). We assessed locomotor activity of KI/KI mice in the open field test after injection with quinpirole, a D2 receptor agonist, at a low (0.05 mg/kg) or high dose (1.0 mg/kg).…”

Section: Reduced Catecholamine Release In Cultured R1441c Ki Chromaffinmentioning

confidence: 99%

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R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice

Tong

Pisani

Martella

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are a common genetic cause of Parkinson's disease (PD). The importance of the R1441 residue in the pathogenesis is highlighted by the identification of three distinct missense mutations. To investigate the pathogenic mechanism underlying LRRK2 dysfunction, we generated a knockin (KI) mouse in which the R1441C mutation is expressed under the control of the endogenous regulatory elements. Homozygous R1441C KI mice appear grossly normal and exhibit no dopaminergic (DA) neurodegeneration or alterations in steady-state levels of striatal dopamine up to 2 years of age. However, these KI mice show reductions in amphetamine (AMPH)-induced locomotor activity and stimulated catecholamine release in cultured chromaffin cells. The introduction of the R1441C mutation also impairs dopamine D2 receptor function, as suggested by decreased responses of KI mice in locomotor activity to the inhibitory effect of a D2 receptor agonist, quinpirole. Furthermore, the firing of nigral neurons in R1441C KI mice show reduced sensitivity to suppression induced by quinpirole, dopamine, or AMPH. Together, our data suggest that the R1441C mutation in LRRK2 impairs stimulated dopamine neurotransmission and D2 receptor function, which may represent pathogenic precursors preceding dopaminergic degeneration in PD brains.Parkinson's disease ͉ knockin ͉ dopamine D2 receptor ͉ amphetamine ͉ quinpirole

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Section: Discussionmentioning

confidence: 65%

Section: Methodsmentioning

confidence: 99%

Section: Reduced Catecholamine Release In Cultured R1441c Ki Chromaffinmentioning

confidence: 99%

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R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice

Tong

Pisani

Martella

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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275

267

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“…It is well known that DJ-1 has multiple functions including anti-oxidant and chaperone functions associated with PD pathogenesis (Menzies et al, 2005;Xu et al, 2005;Zhou et al, 2006). However, DJ-1 deficiency or loss-of-function leads to oxidative stressinduced cell death in vitro and in vivo (Chen et al, 2005;Goldberg et al, 2005;Kim et al, 2005). Although anti-oxidant enzymes have been considered as potential therapeutic agents against oxidative stress-mediated diseases, the enzymes inability to enter cells hinders this despite its apparent potential.…”

Section: Discussionmentioning

confidence: 99%

Transduced Tat-DJ-1 Protein Protects against Oxidative Stress-Induced SH-SY5Y Cell Death and Parkinson Disease in a Mouse Model

Jeong

Kim

Woo

et al. 2012

Molecules and Cells

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Parkinson's disease (PD) is a well known neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compact (SN). Although the exact mechanism remains unclear, oxidative stress plays a critical role in the pathogenesis of PD. DJ-1 is a multifunctional protein, a potent antioxidant and chaperone, the loss of function of which is linked to the autosomal recessive early onset of PD. Therefore, we investigated the protective effects of DJ-1 protein against SH-SY5Y cells and in a PD mouse model using a cell permeable Tat-DJ-1 protein. Tat-DJ-1 protein rapidly transduced into the cells and showed a protective effect on 6-hydroxydopamine (6-OHDA)-induced neuronal cell death by reducing the reactive oxygen species (ROS). In addition, we found that Tat-DJ-1 protein protects against dopaminergic neuronal cell death in 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP)-induced PD mouse models. These results suggest that Tat-DJ-1 protein provides a potential therapeutic strategy for against ROS related human diseases including PD.

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“…14 DJ-1 knock-out (KO) mice and flies showed increased vulnerabilities to neurotoxic agents but no signs of dopaminergic cell death. [15][16][17] PD families may also present missense mutations of DJ-1 in homozygous (L166P, M26I and E64D) and heterozygous forms (A104T and D149A). 14 How these mutants abolish or modify DJ-1 functions is a matter of debate, as a common mechanism of action for the various DJ-1 mutants is still lacking.…”

mentioning

confidence: 99%

Aggresome-forming TTRAP mediates pro-apoptotic properties of Parkinson's disease-associated DJ-1 missense mutations

et al. 2008

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Mutations in PARK7 DJ-1 have been associated with autosomal-recessive early-onset Parkinson's disease (PD). This gene encodes for an atypical peroxiredoxin-like peroxidase that may act as a regulator of transcription and a redox-dependent chaperone. Although large gene deletions have been associated with a loss-of-function phenotype, the pathogenic mechanism of several missense mutations is less clear. By performing a yeast two-hybrid screening from a human fetal brain library, we identified TRAF and TNF receptor-associated protein (TTRAP), an ubiquitin-binding domain-containing protein, as a novel DJ-1 interactor, which was able to bind the PD-associated mutations M26I and L166P more strongly than wild type. TTRAP protected neuroblastoma cells from apoptosis induced by proteasome impairment. In these conditions, endogenous TTRAP relocalized to a detergent-insoluble fraction and formed cytoplasmic aggresome-like structures. Interestingly, both DJ-1 mutants blocked the TTRAP protective activity unmasking a c-jun N-terminal kinase (JNK)-and p38-MAPK (mitogen-activated protein kinase)-mediated apoptosis. These results suggest an active role of DJ-1 missense mutants in the control of cell death and position TTRAP as a new player in the arena of neurodegeneration. Cell Death and Differentiation (2009) Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder, affecting 1-2% of all individuals above the age of 65 years. Its neuropathological hallmark is the selective degeneration of subsets of mesencephalic dopaminergic cells and the formation of proteinaceous cytoplasmic aggregates called Lewy bodies. 1 Several studies implicate the ubiquitin-proteasome system in PD pathogenesis. 2 Synthetic proteasome inhibitors preferentially affect catecholaminergic neurons, leading to cell death. Furthermore, key ubiquitin-proteasome system elements are altered in PD post-mortem brains. [3][4][5] The identification of genes (PARK1-14) associated with familial PD has provided crucial insights into the pathogenic mechanisms. 1 The ubiquitin ligase parkin (PARK2) and the ubiquitin C-terminal hydrolase-L1 (UCH-L1) (PARK5) have been implicated in the ubiquitin-proteasome system function. Interestingly, upon treatment with proteasome inhibitors, they formed insoluble aggregates and were recruited to a juxtanuclear aggresome-like inclusion that resembled the Lewy body. 6,7 Autosomal-recessive early-onset PD has been associated with mutations in PARK7/DJ-1. 8 Functional DJ-1 is a dimer that acts as an atypical peroxiredoxin-like peroxidase as well as a regulator of transcription and a chaperone. 9-12 Interestingly, ectopic DJ-1 expression protects cells from death induced by a variety of insults. 13 DJ-1 loss in humans causes PD. 14 DJ-1 knock-out (KO) mice and flies showed increased vulnerabilities to neurotoxic agents but no signs of dopaminergic cell death. [15][16][17] PD families may also present missense mutations of DJ-1 in homozygous (L166P, M26I and E64D) and heterozygous forms (A104T and D149A)....

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Nigrostriatal Dopaminergic Deficits and Hypokinesia Caused by Inactivation of the Familial Parkinsonism-Linked Gene DJ-1

Cited by 491 publications

References 26 publications

R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice

R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice

Transduced Tat-DJ-1 Protein Protects against Oxidative Stress-Induced SH-SY5Y Cell Death and Parkinson Disease in a Mouse Model

Aggresome-forming TTRAP mediates pro-apoptotic properties of Parkinson's disease-associated DJ-1 missense mutations

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