Transcriptional repression leading to Parkinson's disease
US8603994B2 · kind B2 · utility
Assignee
Inventors
Key dates
| Filing date | Nov 11, 2011 |
| Grant date | Dec 10, 2013 |
| Priority date | — |
| Expiry date | Nov 11, 2031 |
Classification
- Technology area (CPC G)Physics
- CPC primaryG01N2800/2835
- WIPO fieldMeasurement
- WIPO sectorInstruments
Abstract
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.
Source: USPTO / EPO open patent data. Objective bibliographic and citation counts.