Parkin inactivation via PARIS (ZNF746) may lead to neurodegeneration in Parkinson's disease
✍ Scribed by Tien K. Khoo
- Book ID
- 102507572
- Publisher
- John Wiley and Sons
- Year
- 2011
- Tongue
- English
- Weight
- 35 KB
- Volume
- 26
- Category
- Article
- ISSN
- 0885-3185
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✦ Synopsis
At present, the cause of Parkinson's disease (PD) in most people remains unknown. In some cases, however, a monogenic basis has been identified. These genes can be inherited in an autosomal dominant (eg, a-synuclein, LRRK2) or autosomal recessive (eg, parkin, DJ-1, PINK1, ATP13A2) fashion. Parkin is a ubiquitin E3 ligase. Pathophysiological processes identified in PD that include oxidative, nitrosative, and dopaminergic stress can inactivate parkin.
In this article, Shin et al identified a new parkin-interacting substrate, PARIS ( ZNF746), which provides a potential molecular mechanism for neurodegeneration due to parkin inactivation in PD. PARIS is a member of the family of KRAB zinc-finger proteins transcriptional repressors. PARIS has a high degree of homology among human, mouse, and rat species. The results demonstrate the ability of parkin to regulate PARIS via the ubiquitin proteasome system. PARIS was also found to be a major transcriptional repressor of peroxisome proliferator-activated receptor gamma (PPARc) coactivator-1a (PGC-1a) expression. The conditional knockout of parkin in adult mice led to progressive loss of dopamine neurons through PARIS overexpression and transcriptional repression of PGC-1a. PGC-1a is a coactivator that controls the transcription of many genes involved in cellular metabolism. Further study on human brain tissue found PARIS levels were more than doubled in both the striatum and substantia nigra in sporadic PD compared with age-matched controls. Interestingly, PARIS levels were not increased in regions of the brain that are relatively unaffected in PD such as the cerebellum and frontal cortex. This finding suggests upregulation of PARIS is primarily within the nigrostriatal pathway. The authors illustrated that PARIS is an attractive pathogenic substrate in PD. There is uncertainty whether there is differential regional or temporal upregulation of PARIS in PD. The role and magnitude of PARIS in dopaminergic neurodegeneration and its interaction with other systems require further study.