LRRK2: A Pathogenic Gene of Parkinson's Disease (PD)

Parkinson's Disease (PD) is a neurodegenerative disease that cannot be cured. In this article, we review the background information, research insights and applications on LRRK2, a pathogenic gene of PD, providing useful information for further scientific innovation.

Background Information - LRRK2 Gene

Note: the mark “√” represents the corresponding models that available from Cyagen AI Knockout Mouse Model eBank.

Overview of LRRK2 Gene Research

This gene is a member of the leucine-rich repeat kinase (LRRK2) family, and the encoded protein contains ankryin repeat domain, leucine-rich repeat (LRR) domain, kinase domain, dfg-like motif, RAS domain, GTPase domain, mlk-like domain, and WD40 domain. In familial PD, mutations in LRRK2 are the most common compared with those in other genes. Besides, LRRK2-related PD and sporadic PD are difficult to distinguish in terms of the onsite time, disease progression and motor symptoms.

Functional changes associated with LRRK2 mutations include changes in vesicular trafficking and cytoskeleton dynamics, autophagy and lysosomal degradation, neurotransmission, mitochondrial function, and immune and microglial response. It should be noted that the putative molecular mechanisms and degenerative features associated with LRRK2-related PD are not different from most monogenic and sporadic PD.

Figure 1: The structure and function of LRRK2. Domains related to protein-protein interaction are yellow and green, domains related to GTPase function are purple, and the kinase domain is blue. The LRRK2 mutation site marked in green indicates that it has a clear pathogenicity. DOI: 10.1038/s41582-019-0301-2.

LRRK2 is closely related to ERK1/2 and Wnt signaling pathways, all of which affect the functions in the nucleus. Outside the nucleus, the increased protein translation of LRRK2 by inhibiting the protein 4E-BP1 and the increased mitochondrial autophagy leads to autophagy/lysosomal stress. LRRK2 promotes the increase of intracellular calcium ions and activates the ERK1/2-dependent autophagy and down-regulation of dendritic mitochondria. LRRK2 and ERK1/2 also regulate intracellular microtubule kinetics by phosphorylated tau protein, actin, tubulin and so on. LRRK2 also triggers Wnt-β-catenin and ERK1/2 dependent gene transcription changes. Autophagy, transcription, and cytoskeleton effects of mutated LRRK2 should be conducive to shortening ERK1/2-dependent neurite, while altered endosome/vesicle dynamics affects the synaptic function.

Figure 2: LRRK2 signaling pathway

DOI: 10.1016/j.bbadis.2013.11.005.

Expression of LRRK2 Gene in Human Tissues

Figure 3: mRNA relative expression of LRRK2 in humans and mice. Compared with other areas, the expression of this gene is not higher in the human brain, but it is highly expressed in the kidney and spleen. In mice, LRRK2 is also highly expressed in the kidney and spleen. LRRK2 is very highly expressed in the lungs of both humans and mice. (the expression is shown by the normalized relative value rather than the direct RPKM data; such comparison is only limited to the same species rather than in between mice and human). Source: NCBI.

Since the first pathogenic gene of PD was identified in the 1990s, an increasing importance has been attached to the genetic influence on in the pathogenesis of PD. This month, our Weekly Gene series has focused on genes related to a range of neurodegenerative diseases, such as Huntington’s disease (HD), PD, and more. 

Find more PD related mouse models in our selection of research-ready Cyagen Knockout Catalog Models.

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References:

1. Verma M, Steer EK, Chu CT. ERKed by LRRK2: a cell biological perspective on hereditary and sporadic Parkinson's disease. Biochim Biophys Acta. 2014 Aug;1842(8):1273-81. doi: 10.1016/j.bbadis.2013.11.005.

2. Rideout HJ, Chartier-Harlin MC, Fell MJ, Hirst WD, Huntwork-Rodriguez S, Leyns CEG, Mabrouk OS, Taymans JM. The Current State-of-the Art of LRRK2-Based Biomarker Assay Development in Parkinson's Disease. Front Neurosci. 2020 Aug 18;14:865. doi: 10.3389/fnins.2020.00865.

3. Tolosa E, Vila M, Klein C, Rascol O. LRRK2 in Parkinson disease: challenges of clinical trials. Nat Rev Neurol. 2020 Feb;16(2):97-107. doi: 10.1038/s41582-019-0301-2. Epub 2020 Jan 24.