PUBLICATION

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

Authors
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.
ID
ZDB-PUB-210914-13
Date
2021
Source
PLoS Genetics   17: e1009794 (Journal)
Registered Authors
Ahrendt, Reiner, Brand, Michael, Chekuru, Avinash, Hans, Stefan, Kaslin, Jan, Kroehne, Volker, Machate, Anja, Panula, Pertti, Semenova, Svetlana, Winkler, Sylke
Keywords
none
MeSH Terms
  • Larva/metabolism
  • Biogenic Monoamines/metabolism*
  • Zebrafish Proteins/genetics*
  • Gene Deletion*
  • Monoamine Oxidase/metabolism
  • Smell/genetics
  • Swimming
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics*
  • Anxiety/genetics
  • Animals
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • Brain/embryology
  • Brain/enzymology
  • Brain/metabolism*
  • CRISPR-Cas Systems
(all 16)
PubMed
34516550 Full text @ PLoS Genet.
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.
Genes / Markers
Figures
Figure Gallery (4 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
lrrk2tud113/tud113standard conditions26+ somites
lrrk2tud113/tud113standard conditionsDay 5
lrrk2tud113/tud113standard conditionsDay 5
lrrk2tud113/tud113standard conditionsDay 5
lrrk2tud113/tud113standard conditionsDay 5
lrrk2tud113/tud113standard conditionsDay 5
lrrk2tud113/tud113standard conditionsDay 5
lrrk2tud113/tud113standard conditionsDay 5
lrrk2tud113/tud113standard conditionsDay 5
lrrk2tud113/tud113standard conditionsDay 5
1 - 10 of 19
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
tud112
    		Point Mutation
    tud113
      		Small Deletion
      1 - 2 of 2
      Show
      Human Disease / Model
      Human Disease Fish Conditions Evidence
      Parkinson's diseaselrrk2tud113/tud113standard conditionsTAS
      1 - 1 of 1
      Show
      Sequence Targeting Reagents
      Target Reagent Reagent Type
      lrrk2CRISPR1-lrrk2,slc2a13bCRISPR
      lrrk2CRISPR4-lrrk2CRISPR
      lrrk2MO8-lrrk2MRPHLNO
      lrrk2MO9-lrrk2MRPHLNO
      slc2a13bCRISPR1-lrrk2,slc2a13bCRISPR
      1 - 5 of 5
      Show
      Fish
      Fish
      AB
      lrrk2tud113/tud113
      lrrk2tud113/tud113
      1 - 3 of 3
      Show
      Antibodies
      Orthology
      No data available
      Engineered Foreign Genes
      No data available
      Mapping
      No data available
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      Citation
      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. 17:e1009794.