Loss ofparlaFunction Results in Inactivity, OlfactoryImpairment, and Dopamine Neuron Loss in Zebrafish

Abstract:

The presenilin-associated rhomboid-like (PARL) gene was found to contribute to mitochon-drial morphology and function and was linked to familial Parkinson’s disease (PD). ThePARLgeneproduct is a mitochondrial intramembrane cleaving protease that acts on a number of mitochondrialproteins involved in mitochondrial morphology, apoptosis, and mitophagy. To date, functional andgenetic studies ofPARLhave been mainly performed in mammals. However, little is known aboutPARLfunction and its role in dopaminergic (DA) neuron development in vertebrates. The zebrafishgenome comprises twoPARLparalogs:parlaandparlb. Here, we established a loss-of-function muta-tion inparlavia CRISPR/Cas9-mediated mutagenesis. We examined DA neuron numbers in the adultbrain and expression of genes associated with DA neuron function in larvae and adults. We showthat loss ofparlafunction results in loss of DA neurons, mainly in the olfactory bulb. Changes inthe levels oftyrosine hydroxylasetranscripts supported this neuronal loss. Expression offis1, a geneinvolved in mitochondrial fission, was increased inparlamutants. Finally, we showed that loss ofparlafunction translates into impaired olfaction and altered locomotion parameters. These resultssuggest a role forparlain the development and/or maintenance of DA neuron function in zebrafish.

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