Loss of parla Function Results in Inactivity, Olfactory Impairment, and Dopamine Neuron Loss in Zebrafish.

Abstract

The presenilin-associated rhomboid-like (PARL) gene was found to contribute to mitochondrial morphology and function and was linked to familial Parkinson’s disease (PD). The PARL gene product is a mitochondrial intramembrane cleaving protease that acts on a number of mitochondrial proteins involved in mitochondrial morphology, apoptosis, and mitophagy. To date, functional and genetic studies of PARL have been mainly performed in mammals. However, little is known about PARL function and its role in dopaminergic (DA) neuron development in vertebrates. The zebrafish genome comprises two PARL paralogs: parla and parlb. Here, we established a loss-of-function mutation in parla via CRISPR/Cas9-mediated mutagenesis. We examined DA neuron numbers in the adult brain and expression of genes associated with DA neuron function in larvae and adults. We show that loss of parla function results in loss of DA neurons, mainly in the olfactory bulb. Changes in the levels of tyrosine hydroxylase transcripts supported this neuronal loss. Expression of fis1, a gene involved in mitochondrial fission, was increased in parla mutants. Finally, we showed that loss of parla function translates into impaired olfaction and altered locomotion parameters. These results suggest a role for parla in the development and/or maintenance of DA neuron function in zebrafish.