Caenorhabditis elegans as an Experimental Model Organism to Study Parkinson's Disease-Related Genes

Springer, Wolfdieter (2005): Caenorhabditis elegans as an Experimental Model Organism to Study Parkinson's Disease-Related Genes: Functional Analysis of Parkin and alpha-Synuclein. Dissertation, LMU München: Fakultät für Chemie und Pharmazie

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, mainly characterized by motor dysfunctions resulting from massive and selective loss of dopaminergic neurons. Mutations in the human parkin gene, which encodes an E3 ubiquitin ligase, are the most frequent causes of hereditary PD, leading to autosomal-recessive juvenile Parkinsonism. However, the cell biological role of Parkin and the molecular pathogenic mechanisms by which mutations cause PD are unclear. In this study, the Caenorhabditis elegans parkin ortholog, pdr-1, was identified and characterized in detail. PDR-1 is functionally conserved, since it physically associates and cooperates with enzymes of the ubiquitylation/degradation system to mediate ubiquitin conjugation. Strikingly, in contrast to pdr-1 loss-of-function mutants, the in-frame deletion mutant protein PDR-1(delaa24-247) still interacts with its co-enzymes, and moreover, the corresponding mutant pdr-1(lg103) is hypersensitive towards misfolded protein conditions. In this mutant, both cytosolic stress conferred by overexpression of mutant human alpha-synuclein, a gene linked to autosomal-dominant forms of PD, as well as endoplasmatic reticulum (ER)-derived folding stress result in severe developmental defects and lethality. Although expression of pdr-1 is regulated by all three activators of the unfolded protein response (UPR), IRE-1, PEK-1, and ATF-6, genetic analyses established a function of PDR-1 in parallel to IRE-1 signalling. Therefore, PDR-1/Parkin plays an essential role in the regulation of different proteotoxic stress pathways: it contributes to the ER-specific UPR, but also participates in the cytosolic detoxification of protein aggregates, including alpha-synuclein. The truncated protein PDR-1(delaa24-247) seems to mediate a toxic misfunction by sequestering critical components of the protein folding/degradation machinery, which is related to the stress hypersensitivity in the pdr-1(lg103) mutant. In this study, an experimental animal system was established which is well suited to identify modifiers of toxicity and relevant compounds. Such studies might allow to dissect the molecular and cellular pathways involved in the pathogenesis of PD and to identify potential therapeutic drug targets.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: C. elegans, Parkinson's Disease, Parkin, Synuclein, Ubiquitin
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 540 Chemie
• Fakultäten: Fakultät für Chemie und Pharmazie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 7. Juli 2005
• 1. Bericht­erstatter:in: Baumeister, Ralf