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

Stefano Suzzi; Reiner Ahrendt; Stefan Hans; Svetlana A Semenova; Avinash Chekuru; Paul Wirsching; Volker Kroehne; Saygın Bilican; Shady Sayed; Sylke Winkler; Sandra Spieß; Anja Machate; Jan Kaslin; Pertti Panula; Michael Brand

doi:10.1371/journal.pgen.1009794

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

PLoS Genet. 2021 Sep 13;17(9):e1009794. doi: 10.1371/journal.pgen.1009794. eCollection 2021 Sep.

Authors

Affiliations

¹ Center for Molecular and Cellular Bioengineering (CMCB), Center for Regenerative Therapies Dresden (CRTD), Technische Universität (TU) Dresden, Dresden, Germany.
² Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
³ Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Dresden, Germany.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anxiety / genetics
Biogenic Monoamines / metabolism*
Brain / embryology
Brain / enzymology
Brain / metabolism*
CRISPR-Cas Systems
Gene Deletion*
Larva / metabolism
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics*
Monoamine Oxidase / metabolism
Smell / genetics
Swimming
Zebrafish / embryology
Zebrafish / genetics*
Zebrafish Proteins / genetics*

Substances

Biogenic Monoamines
Zebrafish Proteins
Monoamine Oxidase
LRRK2 protein, zebrafish
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2

Grants and funding

This work was supported by project grants of: the Fritz Thyssen Foundation (grant “ZF-Park: Entwicklung von Zebrafish-Modellsystemen der Parkinson’schen Erkrankungen durch diverse Genetik im LRKK2-Gen“), the German Research Foundation (Deutsche Forschungsgemeinschaft, project numbers BR 1746/6 and BR 1746/3), and the European Union through an ERC advanced grant (Zf-BrainReg) to MB; the Sigrid Juselius Foundation and the Jane and Aatos Erkko Foundation to PP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.