RT Journal Article
SR Electronic
T1 Loss of <em>lrrk2</em> impairs dopamine catabolism, cell proliferation, and neuronal regeneration in the zebrafish brain
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 140608
DO 10.1101/140608
A1 Suzzi, Stefano
A1 Ahrendt, Reiner
A1 Hans, Stefan
A1 Semenova, Svetlana A.
A1 Bilican, Saygın
A1 Sayed, Shady
A1 Winkler, Sylke
A1 Spieß, Sandra
A1 Kaslin, Jan
A1 Panula, Pertti
A1 Brand, Michael
YR 2017
UL http://biorxiv.org/content/early/2017/08/01/140608.abstract
AB LRRK2 mutations are a major cause of Parkinson’s 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.