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Neurochem Res. 2019 Jun;44(6):1446-1459. doi: 10.1007/s11064-018-2650-4. Epub 2018 Oct 5.

Differences in Stability, Activity and Mutation Effects Between Human and Mouse Leucine-Rich Repeat Kinase 2.

Author information

1
Laboratory of Neurogenetics, Cell Biology and Gene Expression Section, NIA, NIH, Bethesda, MD, 20892, USA.
2
Department of Neurology, SUNY at Stony Brook, Health Science Center, T12-020, Stony Brook, NY, 11794-8121, USA.
3
Sanford Burnham Prebys Medicial Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
4
Medical College of Wisconsin, Medical School, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA.
5
Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
6
Laboratory of Neurogenetics, Cell Biology and Gene Expression Section, NIA, NIH, Bethesda, MD, 20892, USA. cookson@mail.nih.gov.
7
Laboratory of Neurogenetics, Cell Biology and Gene Expression Section, National Institute on Aging, NIH, 35 Convent Drive, Room 1A-116, Bethesda, MD, 20892-3707, USA. cookson@mail.nih.gov.

Abstract

Mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene have been implicated in the pathogenesis of Parkinson's disease (PD). Identification of PD-associated LRRK2 mutations has led to the development of novel animal models, primarily in mice. However, the characteristics of human LRRK2 and mouse Lrrk2 protein have not previously been directly compared. Here we show that proteins from different species have different biochemical properties, with the mouse protein being more stable but having significantly lower kinase activity compared to the human orthologue. In examining the effects of PD-associated mutations and risk factors on protein function, we found that conserved substitutions such as G2019S affect human and mouse LRRK2 proteins similarly, but variation around position 2385, which is not fully conserved between humans and mice, induces divergent in vitro behavior. Overall our results indicate that structural differences between human and mouse LRRK2 are likely responsible for the different properties we have observed for these two species of LRRK2 protein. These results have implications for disease modelling of LRRK2 mutations in mice and on the testing of pharmacological therapies in animals.

KEYWORDS:

Kinase activity; Level of expression; Mouse model; Parkinson’s disease; Protein stability

PMID:
30291536
PMCID:
PMC6450775
[Available on 2020-06-01]
DOI:
10.1007/s11064-018-2650-4
[Indexed for MEDLINE]

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