Loss of <i>parla</i> Function Results in Inactivity, Olfactory Impairment, and Dopamine Neuron Loss in Zebrafish
The presenilin-associated rhomboid-like (<i>PARL</i>) gene was found to contribute to mitochondrial morphology and function and was linked to familial Parkinson’s disease (PD). The <i>PARL</i> gene product is a mitochondrial intramembrane cleaving protease that acts on a numb...
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| Format: | Article |
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MDPI AG
2021-02-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/9/2/205 |
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| author | Rawan Merhi Michael Kalyn Amanda Zhu-Pawlowsky Marc Ekker |
| author_facet | Rawan Merhi Michael Kalyn Amanda Zhu-Pawlowsky Marc Ekker |
| author_sort | Rawan Merhi |
| collection | DOAJ |
| description | The presenilin-associated rhomboid-like (<i>PARL</i>) gene was found to contribute to mitochondrial morphology and function and was linked to familial Parkinson’s disease (PD). The <i>PARL</i> 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 <i>PARL</i> have been mainly performed in mammals. However, little is known about <i>PARL</i> function and its role in dopaminergic (DA) neuron development in vertebrates. The zebrafish genome comprises two <i>PARL</i> paralogs: <i>parla</i> and <i>parlb</i>. Here, we established a loss-of-function mutation in <i>parla</i> 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 <i>parla</i> function results in loss of DA neurons, mainly in the olfactory bulb. Changes in the levels of <i>tyrosine hydroxylase</i> transcripts supported this neuronal loss. Expression of <i>fis1</i>, a gene involved in mitochondrial fission, was increased in <i>parla</i> mutants. Finally, we showed that loss of <i>parla</i> function translates into impaired olfaction and altered locomotion parameters. These results suggest a role for <i>parla</i> in the development and/or maintenance of DA neuron function in zebrafish. |
| first_indexed | 2024-03-09T00:45:55Z |
| format | Article |
| id | doaj.art-ac88ce66bd5e413cab9718cc7cbe2198 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-09T00:45:55Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
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| series | Biomedicines |
| spelling | doaj.art-ac88ce66bd5e413cab9718cc7cbe21982023-12-11T17:30:31ZengMDPI AGBiomedicines2227-90592021-02-019220510.3390/biomedicines9020205Loss of <i>parla</i> Function Results in Inactivity, Olfactory Impairment, and Dopamine Neuron Loss in ZebrafishRawan Merhi0Michael Kalyn1Amanda Zhu-Pawlowsky2Marc Ekker3Department of Biology, Faculty of Science, University of Ottawa, Ottawa, ON K1N 6N5, CanadaDepartment of Biology, Faculty of Science, University of Ottawa, Ottawa, ON K1N 6N5, CanadaDepartment of Biology, Faculty of Science, University of Ottawa, Ottawa, ON K1N 6N5, CanadaDepartment of Biology, Faculty of Science, University of Ottawa, Ottawa, ON K1N 6N5, CanadaThe presenilin-associated rhomboid-like (<i>PARL</i>) gene was found to contribute to mitochondrial morphology and function and was linked to familial Parkinson’s disease (PD). The <i>PARL</i> 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 <i>PARL</i> have been mainly performed in mammals. However, little is known about <i>PARL</i> function and its role in dopaminergic (DA) neuron development in vertebrates. The zebrafish genome comprises two <i>PARL</i> paralogs: <i>parla</i> and <i>parlb</i>. Here, we established a loss-of-function mutation in <i>parla</i> 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 <i>parla</i> function results in loss of DA neurons, mainly in the olfactory bulb. Changes in the levels of <i>tyrosine hydroxylase</i> transcripts supported this neuronal loss. Expression of <i>fis1</i>, a gene involved in mitochondrial fission, was increased in <i>parla</i> mutants. Finally, we showed that loss of <i>parla</i> function translates into impaired olfaction and altered locomotion parameters. These results suggest a role for <i>parla</i> in the development and/or maintenance of DA neuron function in zebrafish.https://www.mdpi.com/2227-9059/9/2/205Parkinson’s disease<i>parla</i>dopaminergic neuronsmitochondriagene expressionlocomotor |
| spellingShingle | Rawan Merhi Michael Kalyn Amanda Zhu-Pawlowsky Marc Ekker Loss of <i>parla</i> Function Results in Inactivity, Olfactory Impairment, and Dopamine Neuron Loss in Zebrafish Biomedicines Parkinson’s disease <i>parla</i> dopaminergic neurons mitochondria gene expression locomotor |
| title | Loss of <i>parla</i> Function Results in Inactivity, Olfactory Impairment, and Dopamine Neuron Loss in Zebrafish |
| title_full | Loss of <i>parla</i> Function Results in Inactivity, Olfactory Impairment, and Dopamine Neuron Loss in Zebrafish |
| title_fullStr | Loss of <i>parla</i> Function Results in Inactivity, Olfactory Impairment, and Dopamine Neuron Loss in Zebrafish |
| title_full_unstemmed | Loss of <i>parla</i> Function Results in Inactivity, Olfactory Impairment, and Dopamine Neuron Loss in Zebrafish |
| title_short | Loss of <i>parla</i> Function Results in Inactivity, Olfactory Impairment, and Dopamine Neuron Loss in Zebrafish |
| title_sort | loss of i parla i function results in inactivity olfactory impairment and dopamine neuron loss in zebrafish |
| topic | Parkinson’s disease <i>parla</i> dopaminergic neurons mitochondria gene expression locomotor |
| url | https://www.mdpi.com/2227-9059/9/2/205 |
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