LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors

Kelly M. Hinkle, Mei Yue, Bahareh Behrouz, Justus C. Dächsel, Sarah J. Lincoln, Erin E. Bowles, Joel E. Beevers, Brittany Dugger, Beate Winner, Iryna Prots, Caroline B. Kent, Kenya Nishioka, Wen Lang Lin, Dennis W. Dickson, Christopher J. Janus, Matthew J. Farrer, Heather L. Melrose

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

Mutations in the LRRK2 gene are the most common cause of genetic Parkinson's disease. Although the mechanisms behind the pathogenic effects of LRRK2 mutations are still not clear, data emerging from in vitro and in vivo models suggests roles in regulating neuronal polarity, neurotransmission, membrane and cytoskeletal dynamics and protein degradation. We created mice lacking exon 41 that encodes the activation hinge of the kinase domain of LRRK2. We have performed a comprehensive analysis of these mice up to 20 months of age, including evaluation of dopamine storage, release, uptake and synthesis, behavioral testing, dendritic spine and proliferation/neurogenesis analysis. Our results show that the dopaminergic system was not functionally comprised in LRRK2 knockout mice. However, LRRK2 knockout mice displayed abnormal exploratory activity in the open-field test. Moreover, LRRK2 knockout mice stayed longer than their wild type littermates on the accelerated rod during rotarod testing. Finally, we confirm that loss of LRRK2 caused degeneration in the kidney, accompanied by a progressive enhancement of autophagic activity and accumulation of autofluorescent material, but without evidence of biphasic changes.

Original languageEnglish (US)
Article number25
JournalMolecular neurodegeneration
Volume7
Issue number1
DOIs
StatePublished - 2012

Keywords

  • Autophagy
  • Dopamine
  • Kidney
  • Knockout
  • Microdialysis
  • Motor co-ordination
  • Neuropathology
  • Open-field
  • Parkinsons disease

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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    Hinkle, K. M., Yue, M., Behrouz, B., Dächsel, J. C., Lincoln, S. J., Bowles, E. E., Beevers, J. E., Dugger, B., Winner, B., Prots, I., Kent, C. B., Nishioka, K., Lin, W. L., Dickson, D. W., Janus, C. J., Farrer, M. J., & Melrose, H. L. (2012). LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors. Molecular neurodegeneration, 7(1), [25]. https://doi.org/10.1186/1750-1326-7-25