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


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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    • "These genes are all regulated by the transcription factor PGC-1 a, a positive regulator of mitochondrial biogenesis and cellular antioxidant responses [50]. Interestingly the PD-linked gene Parkin appears to be a positive regulator of PGC-1 a, by constantly degrading PARIS (Parkin interacting substrate), a negative regulator of PGC-1 a. Mutations in Parkin can increase PARIS protein levels leading to decreased PGC-1 a and associated energetic deficits [51]. Finally, a recent study has shown that elevated mitochondrial bioenergetics and axonal arborization size could be key contributors to the vulnerability of SNpc mDA neurons [52]. "
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    ABSTRACT: The homeoprotein Engrailed (Engrailed-1/Engrailed-2, collectively En1/2) is not only a survival factor for mesencephalic dopaminergic (mDA) neurons during development, but continues to exert neuroprotective and physiological functions in adult mDA neurons. Loss of one En1 allele in the mouse leads to progressive demise of mDA neurons in the ventral midbrain starting from 6weeks of age. These mice also develop Parkinson disease-like motor and non-motor symptoms. The characterization of En1 heterozygous mice have revealed striking parallels to central mechanisms of Parkinson disease pathogenesis, mainly related to mitochondrial dysfunction and retrograde degeneration. Thanks to the ability of homeoproteins to transduce cells, En1/2 proteins have also been used to protect mDA neurons in various experimental models of Parkinson disease. This neuroprotection is partly linked to the ability of En1/2 to regulate the translation of certain nuclear-encoded mitochondrial mRNAs for complex I subunits. Other transcription factors that govern mDA neuron development (e.g. Foxa1/2, Lmx1a/b, Nurr1, Otx2, Pitx3) also continue to function for the survival and maintenance of mDA neurons in the adult and act through partially overlapping but also diverse mechanisms.
    FEBS letters 10/2015; DOI:10.1016/j.febslet.2015.10.002 · 3.17 Impact Factor
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    • "additional functions assigned to either PINK1 or parkin include regulation of mitochondria along neuronal axons (Weihofen et al. 2009; Liu et al. 2012; Birsa et al. 2014) and control of mitochondrial biogenesis (Pacelli et al. 2011; Shin et al. 2011). There are also important data supporting the idea that parkin can play an important role in ERmitochondrial cross talk (Van Laar et al. 2015), including control of the translocation of a subset of mitochondrial proteins to the ER during mitophagy (Saita et al. 2013), suggesting that parkin may impact multiple organelles in the neuron. "
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    ABSTRACT: Substantial progress has been made in the genetic basis of Parkinson's disease (PD). In particular, by identifying genes that segregate with inherited PD or show robust association with sporadic disease, and by showing the same genes are found on both lists, we have generated an outline of the cause of this condition. Here, we will discuss what those genes tell us about the underlying biology of PD. We specifically discuss the relationships between protein products of PD genes and show that common links include regulation of the autophagy-lysosome system, an important way by which cells recycle proteins and organelles. We also discuss whether all PD genes should be considered to be in the same pathway and propose that in some cases the relationships are closer while in other cases the interactions are more distant and might be considered separate. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 07/2015; DOI:10.1111/jnc.13266 · 4.28 Impact Factor
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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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