The human gene ZNF746, also known as PARIS, has been recently implicated in early-onset Parkinson disease. ZNF746 is a transcriptional regulator that plays a critical role in the regulation of mitochondrial biogenesis; it is regulated by PINK1 (see FBhh0000009) and PRKN (see FBhh0000008) and acts a transcriptional repressor of PGC-1&agr:, a key regulator of mitochondrial biogenesis (see FBhh0000748). There is no high-scoring ortholog of ZNF746 in Drosophila.
Multiple UAS constructs of human Hsap\ZNF746 have been introduced into flies, including wild-type and an inactive mutant form. Ubiquitous expression of wild-type Hsap\ZNF746 results in semi-lethality; surviving adults exhibit a progressive locomotor defect. Feeding of L-DOPA (FBch0000146) ameliorates both phenotypes. Expression specifically in dopaminergic neurons results in an age-related progressive loss of dopaminergic neuron clusters; the progressive locomotor defect is observed and is ameliorated by feeding of L-DOPA.
The effects of increased or decreased expression of Dmel\park and Dmel\Pink1 on the phenotypes of Hsap\ZNF746 transgenic phenotypes has been assessed. Based on immunoblot analysis, dopaminergic knockdown of park or Pink1 leads to marked accumulation of ZNF746, and reciprocally, ZNF746 levels are significantly decreased in flies overexpressing park or Pink1.
[updated Dec. 2021 by FlyBase; FBrf0222196]
Parkinson disease (PD) is a neurodegenerative disease usually typified by slow onset in mid to late adulthood; there are also early-onset and juvenile forms of the disease. Symptoms worsen over time and include resting tremor, muscular rigidity, bradykinesia [abnormal slowness of movement], and postural instability [impaired balance and coordination]; additional symptoms may include postural abnormalities, dysautonomia [symptoms caused by malfunction of the autonomic nervous system], dystonic cramps, and dementia. Parkinson disease is the second-most common neurodegenerative disease (after Alzheimer disease), affecting approximately 1% of the population over 50 (Polymeropoulos et al., 1996, pubmed:8895469). [from MIM:168600; 2013.07.23]
Parkinson disease is described as early-onset disease if signs and symptoms begin before age 50. Early-onset cases that begin before age 20 may be referred to as juvenile-onset disease. [from Genetics Home Reference, GHR_condition:parkinson-disease, 2015.02.13]
In a study of a large Parkinson disease cohort in China two variants of ZNF746, p.G161D and p.R158H, were significantly associated with early-onset Parkinson disease (Li et al., 2021; pubmed:33723766).
ZNF746 encodes a transcription repressor that specifically binds to the 5'-TATTTT[T/G]-3' consensus sequence on promoters; it represses transcription of PGC-1-alpha, thereby playing a role in regulation of neuron death.
Cellular levels of ZNF746 are regulated by PINK1-mediated phosphorylation and PRKN-dependent ubiquitination; it acts a transcriptional repressor of PGC-1α, a key regulator of mitochondrial biogenesis and antioxidant response (FBrf0245070 and references cited therein).
Based on standard orthology algorithms, there is no gene closely related to human ZNF746 in Drosophila. Dmel\Paris is described as similar to ZNF746 in structure and function (FBrf0233892).
