News & Blog: Article

LRRK2's Importance to Parkinson's Disease (PD)

Contributed by Megan Hans, M.Sc. (Megan earned her Masters from Northwestern and now is Research Assistant Antibody Development at Antibodies Incorporated, where she develops custom antibodies and contributes to the production of our NeuroMab line of antibodies, among which are several anti-LRRK2 abs.)

Understanding LRRK2

Leucine-rich repeat kinase 2, LRRK2, also known as dardarin, is a gene that encodes a large protein (2,527 amino acids) that is involved in cell signaling and protein-protein interactions. LRRK2 is active in the brain and multiple other tissues throughout the body. Studies have indicated that LRRK2 is capable of two types of enzymatic activity, kinase activity and GTPase activity. Kinase activity occurs when the protein assists with the transfer of a phosphate group from ATP to amino acids. GTPase activity occurs when the protein hydrolyzes GTP to GDP. This function of LRRK2 is associated with the ROC domain of the protein which helps control the overall shape of the protein. In addition to the enzymatic activity of LRRK2, studies have shown that this protein contains multiple protein-protein interactive regions which show LRRK2 may function as a scaffolding protein that contributes to the formation of a multiprotein signaling complex. LRRK2 has also been linked to changes in neuronal plasticity, autophagy, and vesicle trafficking.

LRRK2's Apparent Link to Parkinson's Disease

Researchers have linked mutations in the LRRK2 gene to Parkinson's Disease. Parkinson's Disease is a brain disorder that can lead to shaking, stiffness, and difficulty with walking, balance, and coordination. This disease affects more than 10 million people worldwide with approximately 60,000 new diagnoses in the United States alone each year. Scientists have been trying to achieve more understanding around the causes of Parkinson's Disease, with a major focus on the LRRK2 gene mutations associated with the disease. The most prominent mutation in LRRK2 is G2019S. This mutation is located within the kinase domain and has been shown to display increased kinase activity of the protein leading to a gain-of-function phenotype. Due to the increased activity as a result of this mutation, basal autophagic degradation is disrupted.


Chen, M., Wu, R. LRRK 2 gene mutations in the pathophysiology of the ROCO domain and therapeutic targets for Parkinson’s Disease: a review. J Biomed Sci 25, 52 (2018). Image used under Creative Commons License 4.0.)" after the citation to link the open access licence.

Above: Chen, M., Wu, R. LRRK 2 gene mutations in the pathophysiology of the ROCO domain and therapeutic targets for Parkinson's Disease: a review. J Biomed Sci 25, 52 (2018). (Image used under Creative Commons License 4.0.)


On-going LRRK2 Research

While researchers have identified several mutations in the LRRK2 gene to be associated with Parkinson’s Disease, it is still unclear how these mutations will affect individuals living with the disease. It has been shown that the same mutations can generate different pathologies within patients. While more research is being conducted to help elucidate the causes of this phenomenon, scientists believe there could also be environmental factors that could sway the pathologic outcome of mutations in LRRK2, including age, gender, exposure to pesticides, and head trauma.

Preclinical trials have shown that a reduction of LRRK2 activity or expression is neuroprotective, making LRRK2 a prime target for disease modifying treatment. In addition, Parkinson’s Disease patients with mutations in LRRK2 have been shown to closely resemble patients with idiopathic Parkinson’s Disease which suggests delineating the mechanism of LRRK2-PD could provide novel insight into idiopathic Parkinson’s Disease with the potential for LRRK2 directed treatments to be effective for patients with idiopathic PD as well.

Powering Research with anti-LRRK2 Antibodies from NeuroMab

Our anti-LRRK2 antibodies (part of the NeuroMab library) have been used in multiple studies. For example, the N241A/34 antibody was highlighted in a study as the best option for multiple different uses in rat, mouse, and human samples as the antibody of choice for Immunoblot, IP, ICC, and IHC. This study from Davies et al. (see "References" below) highlights the fact that N241A/34 was the only antibody with the sensitivity to selectively detect LRRK2 in human brain lysate amongst all other antibodies that were tested.

Antibodies Incorporated-provided NeuroMabs provide multiple antibodies against LRRK2, including antibodies with specificity against the N-terminus or C-terminus.


Anti-LRRK2 antibody immunoreactivity in rat brain. Davies et al. (Image used under Creative Commons License 4.0.)

 

Anti-LRRK2 antibody immunoreactivity in mouse brain. Davies et al. (Image used under Creative Commons License 4.0.)

 

Western blot of anti-LRRK2 tested in human brain lysates from a series of differential extractions carried out in equal volumes. 100pg human WT LRRK2 recombinant protein used as control. Davies et al. (Image used under Creative Commons License 4.0.)


References

Anand VS, Braithwaite SP: LRRK2 in Parkinson’s disease: biochemical functions. FEBS J. 2009, 276: 6428-6435. 10.1111/j.1742-4658.2009.07341.x

Chen, M., Wu, R. LRRK 2 gene mutations in the pathophysiology of the ROCO domain and therapeutic targets for Parkinson’s disease: a review. J Biomed Sci 25, 52 (2018).

Davies, P., Hinkle, K. M., Sukar, N. N., Sepulveda, B., Mesias, R., Serrano, G., Alessi, D. R., Beach, T. G., Benson, D. L., White, C. L., Cowell, R. M., Das, S. S., West, A. B., & Melrose, H. L. (2013). Comprehensive characterization and optimization of anti-LRRK2 (leucine-rich repeat kinase 2) monoclonal antibodies. The Biochemical journal, 453(1), 101–113.

Li, J., Tan, L. & Yu, J. The role of the LRRK2 gene in Parkinsonism. Mol Neurodegeneration 9, 47 (2014).

Parkinson's Foundation | Better Lives. Together. (2020, September 15). Parkinson’s Foundation.

Patricia Gómez-Suaga, Berta Luzón-Toro, Dev Churamani, Ling Zhang, Duncan Bloor-Young, Sandip Patel, Philip G. Woodman, Grant C. Churchill, Sabine Hilfiker, Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP, Human Molecular Genetics, Volume 21, Issue 3, 1 February 2012, Pages 511–525.

Reference, G. H. (2020, August 17). LRRK2 gene. Genetics Home Reference.

Tolosa, E., Vila, M., Klein, C. et al. LRRK2 in Parkinson disease: challenges of clinical trials. Nat Rev Neurol 16, 97–107 (2020).

Zach, S. (2010, October 7). Signal Transduction Protein Array Analysis Links LRRK2 to Ste20 Kinases and PKC Zeta That Modulate Neuronal Plasticity. Plos One.