Zinc finger protein 746 (ZNF746)

Zinc finger protein 746 (ZNF746), also known as Parkin-interacting substrate (PARIS), is a transcriptional repressor containing a KRAB domain and C2HC/C2H2-type zinc finger domains, with wide tissue expression but notable accumulation in the brains of Parkinson’s disease patients[3][4][5][6]. ZNF746 is a substrate of the E3 ubiquitin ligase parkin; when parkin is inactive, ZNF746 levels rise, leading to repression of PGC-1α and its target genes such as NRF-1, in turn causing mitochondrial dysfunction and promoting neurodegeneration, especially in dopaminergic neurons of the substantia nigra[4][6][2][1]. Overexpression of ZNF746 triggers loss of neuron survival, increased oxidative stress, and cellular senescence in various tissues, linking it not only to Parkinson's disease pathogenesis but potentially also to impaired muscle regeneration and age-related diseases[2][4][1][5]. No approved drugs are currently known to target ZNF746 directly; preclinical interest focuses on its modulation as a strategy to restore mitochondrial function and prevent neuronal loss in Parkinson’s disease and related neurodegenerative conditions[4][6][5].

Other names

PARISParkin-interacting substrateFLJ31413

Transcriptional repression of PGC-1α and subsequent downstream genes (e.g., NRF-1); Binding to insulin response promoter sequences