Caden Costa

Background: Parkinson’s disease (PD) is the 2^nd most prevalent neurodegenerative disorder affecting over 6 million people globally, with a steady increase over the last 30 years.¹ Leucine-rich repeat kinase 2 (LRRK2) gene is one of the most common factors associated with Parkinson’s disease.² The hallmark of disease is the formation of Lewy bodies, through protein misfolding of alpha-synuclein and neuronal cell loss within the substantia nigra of the midbrain.^1,2 Current treatment is targeted at increasing dopamine levels in the midbrain, which does not target the cause of the disease only the symptoms.^1,2 Understanding how LRRK2 intervenes in the process of alpha synuclein aggregation and targeting this gain of function mutation could provide a new avenue for future pharmacological treatment of Parkinson’s disease that is neuroprotective.

Objective: In this narrative review, we explored the mechanisms by which LRRK2 mutations disrupt lysosomal degradation and the potential for LRRK2 inhibition as treatment for Parkinson’s disease.

Search Methods: An online search in PubMed database was conducted from 2018-2024 using the following keywords: “Parkinson’s disease”, “genetics”, “LRRK2”.

Results: Clinical biomarkers HLA-DRA, PLD4 and CTSS were connected to PD and identified as a link to neuroinflammation and lysosomal activity.³ Suggesting that lysosomal activity as a role in the disease pathogenesis. Mitophagy is a lysosomal coordinated degradation of dysfunctional mitochondria. RAB10 is part of the mechanism that initiates mitophagy by binding OPTN, and this binding was greatly impaired by LRRK2 mutation resulting in accumulation of RAB10.⁴ Normal LRRK2 activity protects our cells from excessive lysosomal activity.⁵ Lysosomal function was monitored in cells with LRRK2 mutations, through the presence of Cathepsin B,C,D.⁵ These cathepsins that are associated with lysosomal degradation all had a significant decrease in levels in the presence of mutation.⁵ PFE-360 and MLi2 are two LRRK2 inhibitors that were administered to macaques, which then had their protein levels monitored.⁶ Both inhibitors expressed significant decrease in LRRK2 and RAB10 levels.⁶ DNL201 is a newly developed LRRK2 inhibitor that has undergone phase 1 and 1b clinical trials that was well tolerated by participants.² Astrocytes and fibroblasts from these individuals and Gaucher patients illustrated repair of lysosomal degradation.² Suggesting that LRRK2 inhibition may improve degradative activity by boosting glucocerebrosidase activity and correcting the pathway implicated in lysosomal degradation.²

Conclusions: Studies have shown that LRRK2 is a gain of function mutation that disrupts degradative activity in mitochondria and lysosomes through RAB function. Will improved mitophagy and lysosomal degradation be enough to stop or even reverse the progression of Parkinson’s disease? LRRK2 effects many pathogenic pathways in neurons at the molecular level, so understanding and manipulating LRRK2 function is an important step in treatment of Parkinson’s disease.

Works Cited:         

1. Tolosa E, Garrido A, Scholz SW, Poewe W. Challenges in the diagnosis of Parkinson’s disease. Lancet Neurol. 2021;20(5):385-397. doi:10.1016/S1474-4422(21)00030-2
2. Jennings D, Huntwork-Rodriguez S, Henry AG, et al. Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson’s disease. Sci Transl Med. 2022;14(648):eabj2658. doi:10.1126/scitranslmed.abj2658
3. Karayel O, Virreira Winter S, Padmanabhan S, et al. Proteome profiling of cerebrospinal fluid reveals biomarker candidates for Parkinson’s disease. Cell Rep Med. 2022;3(6):100661. doi:10.1016/j.xcrm.2022.100661
4. Wauters F, Cornelissen T, Imberechts D, et al. LRRK2mutations impair depolarization-induced mitophagy through inhibition of mitochondrial accumulation of RAB10. Autophagy. 2020;16(2):203-222. doi:10.1080/15548627.2019.1603548
5. Yadavalli N, Ferguson SM. LRRK2 suppresses lysosome degradative activity in macrophages and microglia through MiT-TFE transcription factor inhibition. Proc Natl Acad Sci U S A. 2023;120(31):e2303789120. doi:10.1073/pnas.2303789120
6. Wang S, Kelly K, Brotchie JM, Koprich JB, West AB. Exosome markers of LRRK2 kinase inhibition. NPJ Parkinsons Dis. 2020;6(1):32. Published 2020 Nov 13. doi:10.1038/s41531-020-00138-7