Therapeutic Targeting of Autosomal Parkinson’s Disease by Modulation of Leucine-Rich Repeat Kinase 2 (LRRK2) Protein

Abstract

Leucine-Rich Repeat Kinase 2 (LRRK2) is gaining attention as a key therapeutic target for autosomal dominant Parkinson’s disease (PD). The primary genetic aetiology of familial PD, accounting for around 5–6 % of familial cases and 2 % of sporadic cases, is mutations in the LRRK2 gene. The most prevalent mutation, G2019S, increases kinase activity, which phosphorylates important serine residues that control LRRK2 function, such as Ser910 and Ser935, leading to the development of PD. The development of LRRK2 inhibitors has emerged as a key area of study for PD therapy. In preclinical research, these inhibitors have demonstrated promise in reducing PD-related damage by altering the cellular localisation of LRRK2 and reduced phosphorylation. In addition to kinase action, LRRK2 is involved in autophagy and mitochondrial function. This participation implies that PD markers including mitochondrial dysfunction and defective autophagy may be addressed by LRRK2-targeted treatments. Moreover, selective LRRK2 inhibitors show promise in the treatment of PD, and more research into the molecular role of LRRK2 in PD is essential to developing efficient therapies that will improve patient outcomes and reduce the course of the illness. This review discusses the role of LRRK2 in pathogenesis of PD and current treatment approaches, particularly LRRK2 kinase inhibitors, and their potential to slow disease progression, along with recent advancements in clinical trials and future outlooks for improving outcomes in PD.