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

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.