Modifiers of PINK1 function in Parkinson's disease

• Antragsteller: Dr. Norman Kock
• Fachliche Zuordnung: Klinische Neurologie; Neurochirurgie und Neuroradiologie
• Förderung: Förderung von 2006 bis 2009
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 27685545

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.

• DFG-Verfahren: Sachbeihilfen