Modifiers of PINK1 function in Parkinson's disease

Project: DFG ProjectsDFG Individual Projects

Project Details

Description

Parkinson s disease (PD) is associated with loss of dopaminergic cells and genetically linked to proteins that function in the management of cellular stress resulting from protein misfolding and oxidative damage. Mutations in the recently discovered PINK1 gene cause autosomal recessive PD. The main objective of this proposal is to determine the molecular pathway of PINK1 and impact of mutated forms. The marked overlap of dystonia and PD prompted us to study the interplay of PINK1 and TorsinA. Human TorsinA, a mutation in which causes another movement disorder termed early-onset torsion dystonia, is highly expressed in dopaminergic neurons. Previous work has established torsins as having molecular chaperone activity. We hypothesize that chaperone activity of TorsinA may have an impact on mitochondrial resident proteins such as PINK1. These studies are designed to determine the disease-causing pathway in which PINK1 is involved by i) gene expression studies on RNA blood samples obtained from PINK1 mutation carriers, and ii) a yeast two-hybrid screen. To test the hypothesis of a possible interaction of TorsinA with other proteins implicated in PD, we will conduct i) screening of genomic DNA from PD patients for a polymorphism in TorsinA which we have shown to modify TorsinA behavior, and ii) test a direct impact of TorsinA on PINK1 expression levels and function in PINK1 mutant and control fibroblasts and other cell types.

Key findings

Parkinson’s disease (PD) is associated with loss of dopaminergic cells and genetically linked to proteins that function in the management of cellular stress resulting from protein misfolding and oxidative damage. Mutations in the recently discovered PINK1 gene cause autosomal recessive PD. The main objective of this research study was to determine the molecular pathway of PINK1 and impact of mutated forms. We performed a mass spectroscopy analysis, using Stratagene’s Interplay Tandem Affinity Purification (TAP) system to identify novel interactors of PINK1. Several potential interactors have been identified, however confirmation studies are pending. Further, we could demonstrate that human skin fibroblasts containing mutated PINK1 display a mitochondrial dysfunction, with a p.V170G PINK1 mutation having an effect particularly on the respiratory chain.

Statusfinished
Effective start/end date01.01.0631.12.09

UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

DFG Research Classification Scheme

  • 206-07 Clinical Neurology Neurosurgery and Neuroradiology

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