PARIS (ZNF746) Repression of PGC-1α Contributes to Neurodegeneration in Parkinson’s Disease
By Joo-Ho Shin, H. Ko, H. Kang, Yunjong Lee, Olga Pletinkova, Juan C. Troconso, Valina L. Dawson, T. Dawson. Cell, 2011
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SUMMARY 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 novel KRAB and zinc finger protein that accumulates in models of parkin inactivation and in human PD brain. PARIS represses the expression of the transcriptional co-activator, 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 that is PARIS dependent. Moreover overexpression of PARIS leads to the selective loss of DA neurons in the substantia nigra, which is reversed by either parkin or PGC-1α co-expression. The identification of PARIS provides a molecular mechanism for neurodegeneration due to parkin inactivation.
Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Physiology
View Paper: https://www.semanticscholar.org/paper/35220bba166bf206a64d7d2ce3ced818df52ca49
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Citations in the corpus
- Mitochondrial Dysfunction in Neurodegenerative Diseases (2012, background): “There is recent evidence showing an impairment of PGC-1␣ in PD based on findings in microarray studies and transgenic mouse models in which a parkin deficiency leads to impaired PGC-1␣ transcription, which is caused by an accumulation of parkin-interacting substrate (Shin et al., 2011).”
- Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease (2012, background): “More recent studies suggested that parkin can regulate mitochondrial biogenesis through regulation of the levels of PARIS [171], a zinc finger-containing protein functioning as a major transcription repressor of PGC-1 α, the master regulator of mitochondrial biogenesis.”
- Parkinson disease: from pathology to molecular disease mechanisms. (2013, background): “Genes controlling cellular bioenergetics that are expressed in response to peroxisome proliferator-activated receptor g coactivator1a (PGC-1a) are underexpressed in PD, whereas PGC-1a expression is upregulated in fibroblasts from PD patients [113,137,168].”
- Sirt1 and the Mitochondria (2016, background): “Acetylation of PGC-1α occurs at several of its lysine residues and is catalyzed by the ubiquitous histone acetyl transferase General control of amino acid synthesis 5 (GCN5) (Dominy et al., 2010).”
- Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences (2012, positive): “Parkin has recently been shown to induce the proteasomal degradation of PARIS (parkin-interacting substrate), which acts as a transcriptional repressor of PGC-1 a (peroxisome proliferator-activated receptor gamma-co-activator 1-alpha) (Shin et al , 2011).”
- Parkinson Disease Epidemiology, Pathology, Genetics and Pathophysiology (2019, background): “PARKIN also indirectly regulates levels of an important transcriptional regulator, PGC-1alpha, which coordinately regulates the expression of genes required for mitochondrial biogenesis as well as multiple antioxidant defenses(35).”
- The Roles of PINK1, Parkin and Mitochondrial Fidelity in Parkinson's Disease (2015, methodology): “…were identified before Parkin’s link to mitochondria was identified (Scarffe et al., 2014); and, recently, Parkin also was found to ubiquitinate the transcriptional repressor named PARIS, causing it to be degraded by the proteasome and thereby inducing mitochondrial biogenesis (Shin et al., 2011).”