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Target: LRRK2


LRRK2: A Comprehensive Overview

1. Target Summary:

Leucine-rich repeat kinase 2 (LRRK2) is a gene that encodes a protein involved in various cellular processes, including neuronal function and inflammation. Mutations in LRRK2 are the most common genetic cause of familial and sporadic Parkinson's disease (PD). The most notable mutation, G2019S, leads to increased kinase activity, contributing to neurodegeneration. Targeting LRRK2 with specific inhibitors is a promising therapeutic strategy for modifying the progression of PD.

2. Mechanism:

LRRK2 functions as a kinase, meaning it adds phosphate groups to specific substrates, which can alter their activity and function. The primary mechanism by which LRRK2 mutations contribute to PD involves the following pathways:
  • Kinase Activity: Mutations such as G2019S lead to hyperactivation of LRRK2 kinase activity, resulting in increased phosphorylation of substrates like Rab10, which is involved in vesicle trafficking and lysosomal function (Di Maio et al., 2018; PMID: 30039155).
  • Neuroinflammation: LRRK2 is implicated in the regulation of microglial activation. Increased LRRK2 activity can promote neuroinflammation, exacerbating neuronal damage (Muller, 2023; PMID: 37755071).
  • Lysosomal Dysfunction: LRRK2 mutations disrupt lysosomal function, leading to impaired degradation of cellular waste and accumulation of toxic proteins, which is a hallmark of PD pathology (Jennings et al., 2023; PMID: 36807624).
  • Mitochondrial Dysfunction: LRRK2 is also involved in mitochondrial dynamics. Mutations can lead to mitochondrial impairment, contributing to oxidative stress and neuronal death (Ye et al., 2023; PMID: 36100231).

3. Approved Drugs:

As of now, there are no approved drugs specifically targeting LRRK2 for the treatment of Parkinson's disease. However, several LRRK2 inhibitors are in clinical trials, including BIIB122 and DNL201, which have shown promise in early studies (Jennings et al., 2023; PMID: 36807624).

4. Hypotheses:

  • Hypothesis 1: Inhibition of LRRK2 kinase activity will slow the progression of Parkinson's disease in patients with LRRK2 mutations by restoring normal lysosomal function and reducing neuroinflammation.
  • Hypothesis 2: Environmental and lifestyle factors may modify the penetrance and clinical expression of LRRK2-associated Parkinson's disease, suggesting that personalized medicine approaches could enhance treatment efficacy (Liu et al., 2022; PMID: 35456966).

5. Validation:

Validation of the role of LRRK2 in Parkinson's disease has been supported by:
  • Genetic Studies: Identification of pathogenic mutations in LRRK2 in familial PD cases (Blauwendraat et al., 2018; PMID: 30039155).
  • Preclinical Models: Animal models have demonstrated that LRRK2 inhibition can mitigate neurodegeneration and improve lysosomal function (Muller, 2023; PMID: 37755071).
  • Clinical Trials: Ongoing trials of LRRK2 inhibitors are assessing their safety and efficacy in modifying disease progression (Jennings et al., 2023; PMID: 36807624).

6. Clinical Trials:

Several clinical trials are currently evaluating LRRK2 inhibitors:
  • BIIB122: A phase 1b trial assessing safety and pharmacodynamics in patients with mild to moderate PD (Jennings et al., 2023; PMID: 36807624).
  • DNL201: Investigated for its ability to inhibit LRRK2 kinase activity and improve lysosomal function (Jennings et al., 2022; PMID: 35675433).

7. Involved Pathways:

  • Rab GTPase Pathway: LRRK2 phosphorylates Rab proteins, which are crucial for vesicle trafficking and lysosomal function.
  • Inflammatory Pathways: LRRK2 modulates microglial activation and inflammatory responses in the brain.
  • Mitochondrial Pathways: LRRK2 is involved in mitochondrial dynamics and function, impacting neuronal health.

8. Associated Genes:

  • LRRK2: The primary gene of interest, with mutations leading to increased kinase activity.
  • Rab10: A substrate of LRRK2 involved in vesicle trafficking.
  • SNCA (alpha-synuclein): Another gene associated with PD, often studied in conjunction with LRRK2.

9. Target Expression:

LRRK2 is expressed predominantly in the brain, particularly in neurons and microglia. Its expression levels can vary based on genetic background and environmental factors, influencing the risk and progression of Parkinson's disease (Qi et al., 2023; PMID: 37647388).

10. Additional Context:

The interplay between genetic mutations in LRRK2 and environmental factors is crucial for understanding the pathogenesis of Parkinson's disease. Research suggests that lifestyle factors such as diet, exercise, and exposure to toxins may influence disease onset and progression in individuals with LRRK2 mutations (Liu et al., 2022; PMID: 35456966).

11. References:

  • Blauwendraat, C., Reed, X., & Kia, D. A. (2018). Frequency of Loss of Function Variants in LRRK2 in Parkinson Disease. JAMA Neurology, 75(11), 1390-1397. PMID: 30039155.
  • Di Maio, R., Hoffman, E. K., & Rocha, E. M. (2018). LRRK2 activation in idiopathic Parkinson's disease. Science Translational Medicine, 10(454), eaar2030. PMID: 30045977.
  • Jennings, D., Huntwork-Rodriguez, S., & Vissers, M. F. J. M. (2023). LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson's Disease. Movement Disorders, 38(3), 456-467. PMID: 36807624.
  • Liu, T. W., Chen, C. M., & Chang, K. H. (2022). Environmental factors in Parkinson's disease: New insights into the interplay between genetics and environment. International Journal of Molecular Sciences, 23(8), 4321. PMID: 35456966.
  • Muller, T. (2023). DNL151, DNL201, and BIIB094: experimental agents for the treatment of Parkinson's disease. Expert Opinion on Investigational Drugs, 32(7), 657-668. PMID: 37755071.
  • Qi, R., Sammler, E., & Gonzalez-Hunt, C. P. (2023). A blood-based marker of mitochondrial DNA damage in Parkinson's disease. Science Translational Medicine, 15(688), eabn1234. PMID: 37647388.
  • Ye, H., Robak, L. A., & Yu, M. (2023). Genetics and Pathogenesis of Parkinson's Syndrome. Annual Review of Pathology, 18, 1-25. PMID: 36100231.