TRANSCRIPTIONAL REPRESSION LEADING TO PARKINSON'S DISEASE

摘要

Parkinson's disease is caused by the preferential loss of substantia nigra dopamine neurons. A Parkin Interacting Substrate, PARIS (ZNF746) is identified. The levels of PARIS 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 brain Parkinson's disease patients. 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. Overexpression of PARIS causes 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.

主权项

1. A method to diagnose Parkinson's disease comprising the steps of:
measuring an amount of a component in a sample, wherein the component is selected from the group consisting of Parkin Interacting Substrate, a metabolite of Parkin Interacting Substrate, an mRNA coding for Parkin Interacting Substrate, PGC-1α, and an mRNA coding for PGC-1α; and comparing the amount of the component against a baseline value.