Abstract
LRRK2 mutations are a major cause of Parkinson’s disease. Pathogenicity of LRRK2 loss-of-function is controversial, as knockout in rodents induces no brain-specific effects and knockdown studies in zebrafish are conflicting. Here we show that deletion of the ~60-kbp-long zebrafish Irrk2 locus elicits a pleomorphic, albeit transient brain phenotype in maternal-zygotic mutants (mzLrrk2). Intriguingly, 11-month-old mzLrrk2 adults display increased amine 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 Irrk2 in larvae. Our results demonstrate that Irrk2 knockout has an early neurodevelopmental effect. We report for the first time perturbed amine 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, potentially critical upon challenges like brain injury.
