LRRK2 Targeting Therapies Study

Parkinson's Disease (PD) affects millions of people around the world, but there is currently no effective cure for PD. Studies have found that leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of PD, therefore, LRRK2 inhibitors are considered as promising PD therapeutics. As a leader in the field of neuroscience, Creative Biolabs focuses on developing LRRK2 inhibitors to help you gain a deep understanding of the mechanism of LRRK2 in PD.

Overview of LRRK2

LRRK2 is a multidomain serine-threonine kinase that belongs to the Roco protein family. LRRK2 is expressed in a variety of tissues and is associated with many cellular processes, including neuronal plasticity, mitochondrial function, vesicular trafficking, reverse transcriptase complex regulation, apoptosis, and autophagy regulation. In addition, LRRK2 genetic variants are strongly associated with PD susceptibility, and LRRK2 pathogenic variants often increase kinase activity. More importantly, small-molecule LRRK2 kinase inhibitors that block these activities have been shown to provide neuroprotection in some PD models. Therefore, inhibition of LRRK2 kinase function is a promising PD treatment strategy.

The Role of LRRK2 in PD

Pathological features of PD include aggregation of α-synuclein and the presence of neuronal eosinophilic inclusions. To date, the underlying molecular mechanisms of PD remain unclear. The treatment of PD mainly focuses on suppressing disease symptoms, and no effective treatment strategy has been found so far. In short, disease-modifying therapy is a long and complex task in the field of PD. One of the most important genetic associations in PD cases is an autosomal dominant mutation in the LRRK2 gene, therefore, the development of LRRK2-targeted drugs offers promising prospects for the treatment of PD.

Fig.1 LRRK2 and PD. (Cabezudo, et al., 2020)

LRRK2 Targeting Therapies of PD

In recent years, a variety of LRRK2 targeting strategies have been developed. Inhibition of LRRK2 by small-molecule kinase inhibitors or antisense oligonucleotides (ASOs) has attracted considerable attention. Notably, loss-of-function variants of LRRK2 in humans have been reported to have no negative health effects, suggesting the safety of LRRK2-targeted therapeutic strategies. The use of small-molecule inhibitors was accompanied by inhibition of LRRK2 activity, resulting in slowed α-synuclein aggregation and neurodegeneration in animal models. Currently, a variety of LRRK2 kinase inhibitors have been introduced into clinical trials. Therefore, small-molecule inhibitors are powerful tools for LRRK2 targeting. Another approach to downregulating LRRK2 activity relies on ASOs, as ASOs can reduce LRRK2 expression levels. Furthermore, this strategy has the advantage of treating central nervous system-selective LRRK2 blockade by intraventricular injection, avoiding the adverse effects of peripheral LRRK2 loss.

As a reputable neuroscience service provider, Creative Biolabs specializes in providing services for PD mechanism of action research, including but not limited to animal model establishment and LRRK2 inhibitor development. If you have any difficulties with your PD-related project, please feel free to contact us for professional assistance.

Reference

1. Cabezudo, D.; et al. Multiple-hit hypothesis in Parkinson’s disease: LRRK2 and inflammation. Frontiers in Neuroscience. 2020, 14: 376.