Deletion of lrrk2 causes early developmental abnormalities and age-dependent increase of monoamine catabolism in the zebrafish brain

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Suzzi , S , Ahrendt , R , Hans , S , Semenova , S A , Chekuru , A , Wirsching , P , Kroehne , V , Bilican , S , Sayed , S , Winkler , S , Spiess , S , Machate , A , Kaslin , J , Panula , P & Brand , M 2021 , ' Deletion of lrrk2 causes early developmental abnormalities and age-dependent increase of monoamine catabolism in the zebrafish brain ' , PLoS Genetics , vol. 17 , no. 9 , 1009794 . https://doi.org/10.1371/journal.pgen.1009794

Title: Deletion of lrrk2 causes early developmental abnormalities and age-dependent increase of monoamine catabolism in the zebrafish brain
Author: Suzzi, Stefano; Ahrendt, Reiner; Hans, Stefan; Semenova, Svetlana A.; Chekuru, Avinash; Wirsching, Paul; Kroehne, Volker; Bilican, Saygin; Sayed, Shady; Winkler, Sylke; Spiess, Sandra; Machate, Anja; Kaslin, Jan; Panula, Pertti; Brand, Michael
Contributor: University of Helsinki, Department of Anatomy
University of Helsinki, Helsinki In Vivo Animal Imaging Platform (HAIP)
Date: 2021-09
Language: eng
Number of pages: 30
Belongs to series: PLoS Genetics
ISSN: 1553-7404
URI: http://hdl.handle.net/10138/335944
Abstract: LRRK2 gain-of-function is considered a major cause of Parkinson's disease (PD) in humans. However, pathogenicity of LRRK2 loss-of-function in animal models is controversial. Here we show that deletion of the entire zebrafish lrrk2 locus elicits a pleomorphic transient brain phenotype in maternal-zygotic mutant embryos (mzLrrk2). In contrast to lrrk2, the paralog gene lrrk1 is virtually not expressed in the brain of both wild-type and mzLrrk2 fish at different developmental stages. Notably, we found reduced catecholaminergic neurons, the main target of PD, in specific cell populations in the brains of mzLrrk2 larvae, but not adult fish. Strikingly, age-dependent accumulation of monoamine oxidase (MAO)-dependent catabolic signatures within mzLrrk2 brains revealed a previously undescribed interaction between LRRK2 and MAO biological activities. Our results highlight mzLrrk2 zebrafish as a tractable tool to study LRRK2 loss-of-function in vivo, and suggest a link between LRRK2 and MAO, potentially of relevance in the prodromic stages of PD. Author summary Parkinson's disease is the second most common degenerative disorder of the brain. Mutations of the LRRK2 gene are the most recurrent genetic cause of pathology, and are thought to result in a more active LRRK2 protein, a large enzyme whose biological function is unclear. Therefore, LRRK2 inhibitors are regarded as promising therapeutics. However, mouse models do not reproduce human pathology unless they also lack LRRK1, and there is evidence of dominant negative effects of LRRK2 mutations. Therefore, the characterization of reliable LRRK2 knockout models might provide insights. In our study, we used the zebrafish as a tractable model to study both early developmental and adult phenotypes resulting from the loss of the entire endogenous lrrk2 gene. We found that mutant embryos displayed subtle brain phenotypes, including reduction of catecholaminergic neurons, the main target of human disease, that spontaneously resolved with development, and a late-onset and progressive increase of dopamine and serotonin degradation consistent with increased MAO enzyme activity. Our results suggest that similar defects might occur in the pre-symptomatic stage of the disease in humans, and warrant further evaluation of LRRK2 inhibition in a therapeutic perspective.
Subject: REPEAT KINASE 2
DISEASE-ASSOCIATED MUTATIONS
PARKINSONS-DISEASE
RAT MODEL
PROTEIN
GENE
NEURODEGENERATION
EXPRESSION
VARIANT
IMPAIRMENT
1184 Genetics, developmental biology, physiology
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