PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson's disease

NeuroRegeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Cell (Impact Factor: 32.24). 03/2011; 144(5):689-702. DOI: 10.1016/j.cell.2011.02.010
Source: PubMed

ABSTRACT A hallmark of Parkinson's disease (PD) is the preferential loss of substantia nigra dopamine neurons. Here, we identify a new parkin interacting substrate, PARIS (ZNF746), whose levels are regulated by the ubiquitin proteasome system via binding to and ubiquitination by the E3 ubiquitin ligase, parkin. PARIS is a KRAB and zinc finger protein that accumulates in models of parkin inactivation and in human PD brain. PARIS represses the expression of the transcriptional coactivator, PGC-1α and the PGC-1α target gene, NRF-1 by binding to insulin response sequences in the PGC-1α promoter. Conditional knockout of parkin in adult animals leads to progressive loss of dopamine (DA) neurons in a PARIS-dependent manner. Moreover, overexpression of PARIS leads to the selective loss of DA neurons in the substantia nigra, and this is reversed by either parkin or PGC-1α coexpression. The identification of PARIS provides a molecular mechanism for neurodegeneration due to parkin inactivation.

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    • "Counts of the rare SNCA-007 transcript did not significantly differ between cases and controls. To estimate whether SNCA expression is specially associated with Parkinson's disease or whether Parkinson's disease-linked transcripts are generally perturbed in circulating blood cells of patients with Parkinson's disease, we examined the expression of loci linked to familial Parkinson's disease [PARK7 (also known as DJ-1) and PARK15 (also known as FBXO7)] and ZNF746 (implicated in mediating the effects of mutant PARK2; Shin et al., 2011). Furthermore, the QDPR gene produces an essential cofactor for dopamine biosynthesis and was also evaluated. "
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    ABSTRACT: There are no cures for neurodegenerative diseases and this is partially due to the difficulty of monitoring pathogenic molecules in patients during life. The Parkinson's disease gene α-synuclein (SNCA) is selectively expressed in blood cells and neurons. Here we show that SNCA transcripts in circulating blood cells are paradoxically reduced in early stage, untreated and dopamine transporter neuroimaging-supported Parkinson's disease in three independent regional, national, and international populations representing 500 cases and 363 controls and on three analogue and digital platforms with P < 0.0001 in meta-analysis. Individuals with SNCA transcripts in the lowest quartile of counts had an odds ratio for Parkinson's disease of 2.45 compared to individuals in the highest quartile. Disease-relevant transcript isoforms were low even near disease onset. Importantly, low SNCA transcript abundance predicted cognitive decline in patients with Parkinson's disease during up to 5 years of longitudinal follow-up. This study reveals a consistent association of reduced SNCA transcripts in accessible peripheral blood and early-stage Parkinson's disease in 863 participants and suggests a clinical role as potential predictor of cognitive decline. Moreover, the three independent biobank cohorts provide a generally useful platform for rapidly validating any biological marker of this common disease. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
    Brain 07/2015; 138(Pt 9). DOI:10.1093/brain/awv202 · 9.20 Impact Factor
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    • "These events lead to an increase in the level of intracellular ROS, mitochondrial dysfunction and subsequently to cell damage and neurodegeneration that are commonly associated with alcohol overuse and alcoholism (Chaung et al. 2008; St- Pierre et al. 2006). In addition, decreased activity of PGC- 1a has been associated with numerous neurodegenerative diseases, such as Huntington disease, Alzheimer disease and Parkinson disease (Cui et al. 2006; Qin et al. 2009; Shin et al. 2011; St-Pierre et al. 2006). However, more studies seem to be necessary to establish the mechanism by which ethanol reduces the levels of cAMP. "
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    ABSTRACT: Substance use disorder is an emerging problem concerning to human health, causing severe side effects, including neurotoxicity. The use of illegal drugs and the misuse of prescription or over-the-counter drugs are growing in this century, being one of the major public health problems. Ethanol and cocaine are one of the most frequently used drugs and, according to the National Institute on Drug Abuse, their concurrent consumption is one of the major causes for emergency hospital room visits. These molecules act in the brain through different mechanisms, altering the nervous system function. Researchers have focused the attention not just in the mechanism of action of these drugs, but also in the mechanism by which they damage the nervous tissue (neurotoxicity). Therefore, the goal of the present review is to provide a global perspective about the mechanisms of the neurotoxicity of cocaine and ethanol.
    Neurotoxicity Research 06/2015; 28(3). DOI:10.1007/s12640-015-9536-x · 3.54 Impact Factor
    • "A conditional Cre-loxP exon 7 Parkin-KO mouse was generated that showed DA neurodegeneration after lentiviral delivery of a GFP-tagged Cre recombinase was delivered stereotactically to the midbrain of adult mice (Shin et al., 2011). This mouse model showed a loss of Parkin protein and upregulation of PARIS, which the authors concluded was responsible for DA neuron death (Shin et al., 2011). However, it is unclear if the DA loss in this inducible model led to locomotor deficits. "
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    ABSTRACT: Understanding the function of genes mutated in hereditary forms of Parkinson's disease yields insight into disease etiology and reveals new pathways in cell biology. Although mutations or variants in many genes increase the susceptibility to Parkinson's disease, only a handful of monogenic causes of parkinsonism have been identified. Biochemical and genetic studies reveal that the products of two genes that are mutated in autosomal recessive parkinsonism, PINK1 and Parkin, normally work together in the same pathway to govern mitochondrial quality control, bolstering previous evidence that mitochondrial damage is involved in Parkinson's disease. PINK1 accumulates on the outer membrane of damaged mitochondria, activates Parkin's E3 ubiquitin ligase activity, and recruits Parkin to the dysfunctional mitochondrion. Then, Parkin ubiquitinates outer mitochondrial membrane proteins to trigger selective autophagy. This review covers the normal functions that PINK1 and Parkin play within cells, their molecular mechanisms of action, and the pathophysiological consequences of their loss. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 01/2015; 85(2):257-273. DOI:10.1016/j.neuron.2014.12.007 · 15.05 Impact Factor
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