LRRK2

Leucine-rich repeat kinase 2 (LRRK2), also known as dardarin, from the Basque word "dardara" which means tremor, is a protein that in humans is encoded by the LRRK2 gene. LRRK2 is a multifunctional protein kinase involved in a variety of cellular processes including neurogenesis, neuronal plasticity, and autophagy. It has garnered significant attention due to its association with Parkinson's disease, making it a focal point of neurodegenerative research.

Function

LRRK2 is a large and complex enzyme that belongs to the ROCO protein family, characterized by the presence of a Ras of complex proteins (ROC) domain. It possesses multiple domains including a kinase domain, a GTPase domain, and several protein-protein interaction domains such as the leucine-rich repeat (LRR) and WD40 domains. This unique structure allows LRRK2 to participate in various cellular functions, acting as both a kinase and a GTPase. Its activity is implicated in the regulation of neuronal morphology, vesicle trafficking, mitochondrial function, and cytoskeletal dynamics.

Pathology

Mutations in the LRRK2 gene are the most common genetic cause of Parkinson's disease, accounting for a significant percentage of both familial and sporadic cases. The most well-known mutation, Gly2019Ser, increases the kinase activity of LRRK2, leading to neurodegeneration. The exact mechanisms by which LRRK2 mutations cause neurodegeneration are not fully understood, but they are believed to involve aberrant phosphorylation of substrates, impaired mitochondrial function, and dysregulated autophagy.

Clinical Significance

The discovery of LRRK2's role in Parkinson's disease has made it a promising target for therapeutic intervention. Inhibitors of LRRK2 kinase activity are currently being explored as potential treatments for Parkinson's disease, with the aim of preventing, slowing, or stopping disease progression. Additionally, LRRK2 is being investigated in the context of other neurodegenerative diseases, suggesting a broader relevance of this kinase in neurodegeneration.

Research Directions

Research on LRRK2 continues to evolve, with studies focusing on understanding its normal physiological functions, the pathogenic effects of mutations, and the development of specific inhibitors that can modulate its activity without causing adverse effects. The elucidation of LRRK2's structure has been a significant milestone, providing insights into its enzymatic mechanisms and facilitating the design of targeted therapies.

See Also

• Parkinson's disease
• Protein kinase
• Neurodegeneration
• Autophagy

External Links

• Parkinson's UK: What is LRRK2?