Loss of lrrk2 impairs dopamine catabolism, cell proliferation, and neuronal regeneration in the zebrafish brain

Publikation: Vorabdruck/Dokumentation/BerichtVorabdruck (Preprint)

Beitragende

  • Stefano Suzzi - , Weizmann Institute of Science (Autor:in)
  • Reiner Ahrendt - , Technische Universität Dresden (Autor:in)
  • Stefan Hans - , Center for Regenerative Therapies Dresden (CRTD) (Autor:in)
  • Svetlana A. Semenova - , Eunice Kennedy Shriver National Institute of Child Health and Human Development (Autor:in)
  • Saygın Bilican - , Technische Universität Dresden (Autor:in)
  • Shady Sayed - , Technische Universität Dresden (Autor:in)
  • Sylke Winkler - , Max Planck Institute of Molecular Cell Biology and Genetics (Autor:in)
  • Sandra Spieß - , Technische Universität Dresden (Autor:in)
  • Jan Kaslin - , Monash University (Autor:in)
  • Pertti Panula - , University of Helsinki (Autor:in)
  • Michael Brand - , Center for Regenerative Therapies Dresden (CRTD) (Autor:in)

Abstract

LRRK2 mutations are a major cause of Parkinsons disease. Pathogenicity of LRRK2 loss-of-function is controversial, as knockout in rodents reportedly induces no brain-specific effects and knockdown studies in zebrafish are conflicting. Here we show that CRISPR/Cas9-engineered deletion of the ~60-kbp-long zebrafish lrrk2 locus elicits a pleomorphic, albeit transient brain phenotype in maternal-zygotic mutants (mzLrrk2). Intriguingly, 11-month-old mzLrrk2 adults display increased dopamine and serotonin catabolism. Additionally, we find decreased mitosis in the larval brain and reduced stab injury-induced neuronal regeneration in the adult telencephalon. Finally, hypokinesia associates with loss of lrrk2 in larvae. Our results demonstrate that lrrk2 knockout has an early neurodevelopmental effect, and leads to perturbed dopamine and serotonin catabolism in a LRRK2 knockout. We propose mzLrrk2 zebrafish as a valuable tool to study LRRK2 loss-of-function in vivo, and provide a link between LRRK2 and the control of basal cell proliferation in the brain that may become potentially critical upon challenges like brain injury.

Details

OriginalspracheEnglisch
PublikationsstatusVeröffentlicht - 23 Mai 2017
Extern publiziertJa
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Externe IDs

ORCID /0000-0003-0283-0211/work/142661038

Schlagworte

Schlagwörter

  • neuroscience