Article

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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    • "It is thus proposed that mutation of parkin could results in mitochondrial dysfunction, which may causally link with the pathogenesis of PD. However, knockout of parkin in mice could not faithfully recapitulate the PD phenotype, raising the question of the physiological function and the pathologic role of parkin in PD (Dawson and Dawson, 2010; Johnson et al., 2012; Shin et al., 2011). P62, also known as sequestosome 1, is a shuttle protein transporting polyubiquitinated proteins for both the proteasomal and autophagy/lysosomal dependent degradation (Komatsu et al., 2007; Pankiv et al., 2007; Seibenhener et al., 2004; Wooten et al., 2008). "
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    ABSTRACT: Mutations or inactivation of parkin, an E3 ubiquitin ligase, are associated with familial form or sporadic Parkinson's disease (PD), respectively, which manifested with the selective vulnerability of neuronal cells in substantia nigra (SN) and striatum (STR) regions. However, the underlying molecular mechanism linking parkin with the etiology of PD remains elusive. Here we report that p62, a critical regulator for protein quality control, inclusion body formation, selective autophagy and diverse signaling pathways, is a new substrate of parkin. P62 levels were increased in the SN and STR regions, but not in other brain regions in parkin knockout mice. Parkin directly interacts with and ubiquitinates p62 at the K13 to promote proteasomal degradation of p62 even in the absence of ATG5. Pathogenic mutations, knockdown of parkin or mutation of p62 at K13 prevented the degradation of p62. We further showed that parkin deficiency mice have pronounced loss of tyrosine hydroxylase positive neurons and have worse performance in motor test when treated with 6-hydroxydopamine hydrochloride in aged mice. These results suggest that, in addition to their critical role in regulating autophagy, p62 are subjected to parkin mediated proteasomal degradation and implicate that the dysregulation of parkin/p62 axis may involve in the selective vulnerability of neuronal cells during the onset of PD pathogenesis.
    Preview · Article · Jan 2016 · Protein & Cell
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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.
    Full-text · Article · Oct 2015 · FEBS letters
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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.
    Preview · Article · Jul 2015 · Journal of Neurochemistry
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