Recent advances in targeting LRRK2 for Parkinson's disease treatment

Abstract

Parkinson's disease (PD) is a neurodegenerative disease with severe movement problems. Current treatments mainly focus on symptom management by reducing dopaminergic pathways in the brain. Despite these therapies, ongoing disease progression undermines the effectiveness of prevalent approaches, necessitating exploring alternative methods anchored on genetic factors, notably the leucine-rich repeat kinase 2 (LRRK2) gene. Exploring LRRK2 gene pathogenesis has highlighted various mechanisms that may contribute to treating PD, including protein accumulation, altered cytoskeletal dynamics, neuro-inflammation, autophagy, and mitochondrial dysfunction. Based on the findings, there is an actual correlation between elevated levels of LRRK2 and the biomarkers and assays of PD. Furthermore, research results have suggested inhibiting LRRK2 as a therapeutic intervention targeting pathogenic mechanisms with varying degrees of efficacy. Our review wants to understand how LRRK2 works in the body and its relationship with the occurrence of PD by providing biochemical evidence, LRRK2 gene mutations and pathology, and the role of this gene in the immune system. We also discuss targeted therapies such as kinase inhibitors and Proteolysis targeting chimera and the application of using the LRRK2 protein to diagnose PD and develop bioassay designs. Finally, we mention the clinical trials conducted and the challenges and safety required.

Keywords: Autophagy; LRRK2; Mitochondrial dysfunction; Neuro-inflammation; Neurodegenerative diseases; PROTAC; Parkinson’s disease.

Fig. 1

Illustration of human LRRK2 protein with presently recognized pathogenic mutations linked to PD leads to increased kinase activity. LRRK2 pathologies on Autophagy and Ubiquitin proteasome, pathway, cytoskeletal dynamics, mitochondrial dysfunction, Lewis bodies, and the immune system

Fig. 2

Illustration of LRRk2 expression in different tissue and cell types. In the healthy brain, LRRK2 has expressed at low levels in microglia. In contrast, PD brains observed increased expression levels in LRRK2 and activated microglia, leading to neuroinflammation and dopaminergic neuron death. Despite being associated with gut inflammation, LRRK2 is required for spleen, lung, and kidney health. LRRK2 expression is increased in peripheral immune cells in PD patients leading to increases in cytokine release from monocytes and neutrophils

Fig. 3

Mutant LRRK2 leads to the transmission of α-synuclein from one neuron to another. Mutation in LRRK2 stimulates kinase activity and phosphorylates Rab35, which involves α-synuclein released into the extracellular area by exosomes. These exosomes get into the cytosol of other neurons. Also, Rab7 inhibitions eventually prevent the endosome-lysosomal degradation of α-synuclein aggregates