Bertram, L. & Tanzi, R. E. The genetic epidemiology of neurodegenerative disease. J. Clin. Invest. 1151449–1457 (2005).
Google Scholar
de Lau, L. M. & Breteler, M. M. Epidemiology of Parkinson’s disease. Lancet Neurol. 5525–535 (2006).
Google Scholar
Poewe, W. Non-motor symptoms in Parkinson’s disease. Eur. J. Neurol. 1514–20 (2008).
Google Scholar
Postuma, R. B. et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov. Disord. 301591–1601 (2015).
Google Scholar
Pfeiffer, R. F. Non-motor symptoms in Parkinson’s disease. Parkinsonism Relat. Disord. 22S119–S122 (2016).
Google Scholar
Jankovic, J. Parkinson’s disease: clinical features and diagnosis. J. Neurol. Neurosurg. Psychiatry 79368–376 (2008).
Google Scholar
Poewe, W. The natural history of Parkinson’s disease. J. Neurol. 253VII2–VII6 (2006).
Google Scholar
Schrag, A. & Banks, P. Time of loss of employment in Parkinson’s disease. Mov. Disord. 211839–1843 (2006).
Google Scholar
Schrag, A., Jahanshahi, M. & Quinn, N. How does Parkinson’s disease affect quality of life? A comparison with quality of life in the general population. Mov. Disord. 151112–1118 (2000).
Google Scholar
Azeggagh, S. & Berwick, D. C. The development of inhibitors of leucine-rich repeat kinase 2 (LRRK2) as a therapeutic strategy for Parkinson’s disease: the current state of play. Br. J. Pharmacol. 1791478–1495 (2022).
Google Scholar
Jankovic, J. & Tan, E. K. Parkinson’s disease: etiopathogenesis and treatment. J. Neurol. Neurosurg. Psychiatry 91795–808 (2020).
Google Scholar
Hernandez, D. G., Reed, X. & Singleton, A. B. Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. J. Neurochem. 13959–74 (2016).
Google Scholar
Healy, D. G. et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol. 7583–590 (2008).
Google Scholar
Nalls, M. A. et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat. Genet. 46989–993 (2014).
Google Scholar
Berwick, D. C., Heaton, G. R., Azeggagh, S. & Harvey, K. LRRK2 biology from structure to dysfunction: research progresses, but the themes remain the same. Mol. Neurodegener. 1449 (2019).
Google Scholar
Simpson, C. et al. Prevalence of ten LRRK2 variants in Parkinson’s disease: a comprehensive review. Parkinsonism Relat. Disord. 98103–113 (2022).
Google Scholar
Taymans, J. M. et al. Perspective on the current state of the LRRK2 field. npj Parkinson’s Dis. 9104 (2023).
Google Scholar
Nalls, M. A. et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 181091–1102 (2019).
Google Scholar
Nixon-Abell, J. et al. Protective LRRK2R1398H variant enhances GTPase and Wnt signaling activity. Front. Mol. Neurosci. 918 (2016).
Google Scholar
Trinh, J. et al. Molecular mechanisms defining penetrance of LRRK2-associated Parkinson’s disease. With. The gene. 34103–116 (2022).
Google Scholar
Boecker, C. A. The role of LRRK2 in intracellular organelle dynamics. J. Mol. Biol. 435167998 (2023).
Google Scholar
Steger, M. et al. Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. eLife 5e12813 (2016).
Google Scholar
Homma, Y., Hiragi, S. & Fukuda, M. Rab family of small GTPases: an updated view on their regulation and functions. FEBS J. 28836–55 (2021).
Google Scholar
Fraser, K. B. et al. Ser(P)-1292 LRRK2 in urinary exosomes is elevated in idiopathic Parkinson’s disease. Mov. Disord. 311543–1550 (2016).
Google Scholar
Kuwahara, T. & Iwatsubo, T. The emerging functions of LRRK2 and Rab GTPases in the endolysosomal system. Front. Neurosci. 14227 (2020).
Google Scholar
Steger, M. et al. Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis. eLife 6e31012 (2017).
Google Scholar
Ito, G. et al. Phos-tag analysis of Rab10 phosphorylation by LRRK2: a powerful assay for assessing kinase function and inhibitors. Biochem. J. 4732671–2685 (2016).
Google Scholar
Jeong, G. R. et al. Dysregulated phosphorylation of Rab GTPases by LRRK2 induces neurodegeneration. Mol. Neurodegener. 138 (2018).
Google Scholar
Di Maio, R. et al. LRRK2 activation in idiopathic Parkinson’s disease. Sci. Transl. Med. 10eaar5429 (2018).
Wallings, R. L. et al. WHOPPA enables parallel assessment of leucine-rich repeat kinase 2 and glucocerebrosidase enzymatic activity in Parkinson’s disease monocytes. Front. Cell Neurosci. 16892899 (2022).
Google Scholar
Cho, H. J. et al. MicroRNA-205 regulates the expression of Parkinson’s disease-related leucine-rich repeat kinase 2 protein. Hum. Mol. Genet. 22608–620 (2013).
Google Scholar
Cook, D. A. et al. LRRK2 levels in immune cells are increased in Parkinson’s disease. npj Parkinson’s Dis. 311 (2017).
Google Scholar
Bliederhaeuser, C. et al. LRRK2 contributes to monocyte dysregulation in Parkinson’s disease. Acta Neuropathol. Commun. 4123 (2016).
Google Scholar
Mabrouk, O. S. et al. Quantitative measurements of LRRK2 in human cerebrospinal fluid demonstrates increased levels in G2019S patients. Front. Neurosci. 14526 (2020).
Google Scholar
Virreira Winter, S. et al. Urinary proteome profiling for stratifying patients with familial Parkinson’s disease. EMBO Mol. With. 13e13257 (2021).
Google Scholar
Karayel, O. et al. Proteome profiling of cerebrospinal fluid reveals biomarker candidates for Parkinson’s disease. Cell Rep. With. 3100661 (2022).
Google Scholar
Li, L. et al. Parkinson’s disease involves autophagy and abnormal distribution of cathepsin L. Neurosci. Lett. 48962–67 (2011).
Google Scholar
Yadavalli, N. & Ferguson, S. M. LRRK2 suppresses lysosome degradative activity in macrophages and microglia through MiT-TFE transcription factor inhibition. Proc. Natl Acad. Sci. USA 120e2303789120 (2023).
Google Scholar
Merchant, KM et al. LRRK2 and RECEIVE1 variant carriers have higher urinary bis(monacylglycerol) phosphate concentrations in PPMI cohorts. npj Parkinson’s Dis. 930 (2023).
Google Scholar
Gomes, S. et al. Elevated urine BMP phospholipids in LRRK2 and VPS35 mutation carriers with and without Parkinson’s disease. npj Parkinson’s Dis. 952 (2023).
Google Scholar
Zhao, H. T. et al. LRRK2 antisense oligonucleotides ameliorate α-synuclein inclusion formation in a Parkinson’s disease mouse model. Mol. Ther. Nucleic Acids 8508–519 (2017).
Google Scholar
Jennings, D. et al. Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson’s disease. Sci. Transl. Med. 14eabj2658 (2022).
Google Scholar
Herzig, M. C. et al. LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice. Hum. Mol. Genet. 204209–4223 (2011).
Google Scholar
Miller, G. K. et al. Effects of LRRK2 inhibitors in nonhuman primates. Toxicol. Pathol. 51232–245 (2023).
Google Scholar
Fuji, R. N. et al. Effect of selective LRRK2 kinase inhibition on nonhuman primate lung. Sci. Transl. Med. 7273ra215 (2015).
Google Scholar
Baptista, M. A. S. et al. LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits. Sci. Transl. Med. 12eaav0820 (2020).
Google Scholar
Andersen, M. A. et al. Long-term exposure to PFE-360 in the AAV-α-synuclein rat model: findings and implications. eNeuro 6ENEURO.0453-18 (2019).
Google Scholar
Tian, Y. et al. LRRK2 plays essential roles in maintaining lung homeostasis and preventing the development of pulmonary fibrosis. Proc. Natl Acad. Sci. USA 118e2106685118 (2021).
Google Scholar
Lubben, N. et al. LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology progression. Transl. Neurodegener. 1313 (2024).
Google Scholar
Yang, D. et al. Neurofilament light chain as a mediator between LRRK2 mutation and dementia in Parkinson’s disease. npj Parkinson’s Dis. 9132 (2023).
Google Scholar
Mummery, C. J. et al. Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial. Night. With. 291437–1447 (2023).
Google Scholar
Blair, H. A. Tofersen: first approval. Drugs 831039–1043 (2023).
Google Scholar
Mazur, C. et al. Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging. JCI Insight 4e129240 (2019).
Google Scholar
Jafar-Nejad, P. et al. The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration. Nucleic Acids Res. 49657–673 (2021).
Google Scholar
Fan, Y. et al. R1441G but not G2019S mutation enhances LRRK2 mediated Rab10 phosphorylation in human peripheral blood neutrophils. Acta Neuropathol. 142475–494 (2021).
Google Scholar
Vissers, M. et al. A leucine-rich repeat kinase 2 (LRRK2) pathway biomarker characterization study in patients with Parkinson’s disease with and without LRRK2 mutations and healthy controls. Clin. Transl. Sci. 161408–1420 (2023).
Google Scholar
Eguchi, T. et al. LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis. Proc. Natl Acad. Sci. USA 115E9115–E9124 (2018).
Google Scholar
Sjodin, S. et al. Endo-lysosomal proteins and ubiquitin CSF concentrations in Alzheimer’s and Parkinson’s disease. Alzheimers Res. Ther. 1182 (2019).
Google Scholar
Kuwahara, T. et al. Roles of lysosomotropic agents on LRRK2 activation and Rab10 phosphorylation. Neurobiol. Dis. 145105081 (2020).
Google Scholar
Holden, S. K., Finseth, T., Sillau, S. H. & Berman, B. D. Progression of MDS-UPDRS scores over five years in de novo Parkinson disease from the Parkinson’s Progression Markers Initiative cohort. Mov. Disord. Clin. Pract. 547–53 (2018).
Google Scholar
Boucherie, D. M. et al. Parkinson’s disease drug development since 1999: a story of repurposing and relative success. J. Parkinson Dis. 11421–429 (2021).
Google Scholar
Ross, B. S., Song, Q. & Han, M. Kilo-scale synthesis process for 2′-O-(2-methoxyethyl)-pyrimidine derivatives. Nucleosides Nucleotides Nucleic Acids 24815–818 (2005).
Google Scholar
Yang, J. et al. Solid-phase synthesis of phosphorothioate oligonucleotides using sulfurization byproducts for in situ capping. J. Org. Chem. 8311577–11585 (2018).
Google Scholar
