Overexpression of Parkinson’s disease-associated mutation LRRK2 G2019S in mouse forebrain induces behavioral deficits and α-synuclein pathology

Yulan Xiong, Stewart Neifert, Senthilkumar S. Karuppagounder, Jeannette N. Stankowski, Byoung Dae Lee, Jonathan C. Grima, Guanxing Chen, Han Seok Ko, Yunjong Lee, Debbie Swing, Lino Tessarollo, Ted M. Dawson, Valina L. Dawson

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified as an unambiguous cause of late-onset, autosomal-dominant familial Parkinson’s disease (PD) and LRRK2 mutations are the strongest genetic risk factor for sporadic PD known to date. A number of transgenic mice expressing wild-type or mutant LRRK2 have been described with varying degrees of LRRK2-related abnormalities and modest pathologies. None of these studies directly addressed the role of the kinase domain in the changes observed and none of the mice present with robust features of the human disease. In an attempt to address these issues, we created a conditional LRRK2 G2019S (LRRK2 GS) mutant and a functionally negative control, LRRK2 G2019S/D1994A (LRRK2 GS/DA). Expression of LRRK2 GS or LRRK2 GS/DA was conditionally controlled using the tet-off system in which the presence of tetracycline-transactivator protein (tTA) with a CAMKIIα promoter (CAMKIIα-tTA) induced expression of TetP-LRRK2 GS or TetP-LRRK2 GS/DA in the mouse forebrain. Overexpression of LRRK2 GS in mouse forebrain induced behavioral deficits and α-synuclein pathology in a kinase-dependent manner. Similar to other genetically engineered LRRK2 GS mice, there was no significant loss of dopaminergic neurons. These mice provide an important new tool to study neurobiological changes associated with the increased kinase activity from the LRRK2 G2019S mutation, which may ultimately lead to a better understanding of not only the physiologic actions of LRRK2, but also potential pathologic actions that underlie LRRK2 GS-associated PD.

Original languageEnglish (US)
Article numbere0004
Issue number2
StatePublished - 2017


  • LRRK2
  • Parkinson’s disease
  • Transgenic mice
  • α-synuclein

ASJC Scopus subject areas

  • Neuroscience(all)


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