PgmNr Z6161: Functional Analysis of Parla and Parlb Paralogs in Zebrafish.

Authors:
M. Jung; S. Noble; M. Ekker


Institutes
Center for Advanced Research in Environmental Genomics (CAREG), Department of Biology, University of Ottawa, Ottawa, ON, CA.


Abstract:

            Parkinson’s disease is a highly prevalent multifactorial neurodegenerative disorder caused by a complex cascade of interactions between various genetic and epigenetic factors. Due to this, the majority of cases are termed idiopathic, however, about 10% of PD cases are due to defined genetic factors. Interestingly, both idiopathic and familial cases of PD share mitochondrial dysfunction as a central component in the pathology of the disease. The mitochondrial protease, presenilin-associated rhomboid-like (PARL), is a Parkinson's disease-linked gene, functioning in regulated intramembrane proteolysis in the inner mitochondrial membrane. PARL is associated with diverse processes including mitochondrial dynamics, and is seen to actively inhibit unnecessary apoptosis and mitophagy in Drosophila and yeast. Here, we investigated the role of the two zebrafish parl paralogs, parla and parlb, through transient morpholino mediated loss and stable CRISPR-Cas9 mediated mutagenesis. Our morpholino results show a transient loss of parla and/or parlb function resulted in defects in the dopaminergic neurons, including mild neurodegeneration and mispatterning in the ventral diencephalon. Morphants exhibited extensive cell death throughout the entire body, as well as increased larval mortality. Additionally, for the first time in vertebrates, our results show evidence that the parl genes may function upstream of pink1, in a conserved pathway between Drosophila and zebrafish. In order to study the effects of heritable loss of parl function, parla and/or parlb mutant lines were produced via the CRISPR-Cas9 system. Several mutant zebrafish lines have been identified and current efforts focus on characterizing these mutant lines for further phenotype assessments. This research will shed light on the specific roles played by each of the two parl genes in zebrafish, potentially leading to a better understanding of Parkinson’s disease etiology.



ZFIN Genetics Index
1. parla
2. parlb
3. pink1