eNeuroMar 22, 2017

Overactive Parkinson’s Mutation LRRK2 G2019S in Mouse Thinking Areas Causes Behavior Problems and Protein Build-Up

Regenerative Health Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Apr 6, 2026

Abstract

Overexpression of LRRK2 G2019S in mouse forebrain induced behavioral deficits and α-synuclein pathology in a kinase-dependent manner.

Mutations in the LRRK2 gene are a known cause of late-onset familial Parkinson's disease and a significant risk factor for sporadic cases.
Transgenic mice expressing LRRK2 have exhibited varying degrees of abnormalities but have not shown robust features of human Parkinson's disease.
A new mouse model with conditional expression of LRRK2 G2019S was developed to better understand the kinase domain's role in disease mechanisms.
Overexpression of LRRK2 G2019S led to specific behavioral deficits and α-synuclein accumulation, suggesting a link to disease pathology.
Despite these changes, there was no significant loss of dopaminergic neurons in the mice, indicating a complex relationship between LRRK2 mutations and neurodegeneration.

Simplified

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 CAMKIIpromoter (CAMKII-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. α α

Key numbers

16×

Increase in LRRK2 expression

Overexpression levels in line 569 compared to control.

5×

Increase in LRRK2 expression

Overexpression levels in line 569 compared to control.

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Funding

Competing interests

The authors report no competing financial interests.

PubMed