Parkinson’s disease associated with mutations in the LRRK2 gene. Approaches to therapy

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Leucine-rich repeat kinase 2 (LRRK2) belongs to the subfamily of tyrosine kinase–like kinases, the main function of which is to catalyze the transfer of γ-phosphate from ATP to the substrate in the cell due to the kinase domains. The exact functions of LRRK2 in the cell remain unknown. It has been shown that mutations in the LRRK2 gene, which are the cause of the development of the most common autosomal dominant form of neurodegenerative disease, Parkinson’s disease (PD), mainly lead to a pathological increase in kinase activity. This review describes the structure of LRRK2, the functional activity of LRRK2 kinase in the form of a monomer, dimer and even a tetramer, and describes the effect of mutations in the LRRK2 gene on the structure and kinase activity of the LRRK2 enzyme. Understanding the structure and functions of LRRK2 opens up new prospects for using it as a target for PD therapy.

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作者简介

T. Usenko

Petersburg Nuclear Physics Institute named by B. P. Konstantinov of NRC “Kurchatov Institute”; First Pavlov State Medical University of St. Petersburg

编辑信件的主要联系方式.
Email: usenko_ts@pnpi.nrcki.ru
俄罗斯联邦, Gatchina, 188300; St. Petersburg, 197022

S. Pchelina

Petersburg Nuclear Physics Institute named by B. P. Konstantinov of NRC “Kurchatov Institute”; First Pavlov State Medical University of St. Petersburg

Email: usenko_ts@pnpi.nrcki.ru
俄罗斯联邦, Gatchina, 188300; St. Petersburg, 197022

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2. Fig. 1. Schematic representation of LRRK2 with functional domains and locations of the most common mutations and risk variants (*) in PD. LRRK2 domains: ARM (armadillo), ankyrin (ANK), leucine-rich repeats (LRR), Ras-like GTPase (Ras-of-complex (ROC) domain), kinase, scaffold domain (C-terminus of ROC (COR)) and WD40 [26] (Creative Commons Attribution License 4.0, with modifications).

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3. Fig. 2. Schematic diagram of the mechanism of LRRK2 activation via Rab29. LRRK2 is mainly present in the cytosol in a monomeric GTP-bound form, which is able to form a stable complex with 14-3-3 proteins. Binding of LRRK2 to Rab29 induces membrane localization of LRRK2. On the membrane, GTP is hydrolyzed, LRRK2 dimerizes, which leads to activation of the LRRK2 kinase domain and initiation of substrate phosphorylation. The low affinity of LRRK2 for GTP promotes rapid release of GTP, rebinding of GDP, subsequent monomerization of LRRK2 and return to the cytosol [26] (Creative Commons Attribution License 4.0, with modifications).

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4. Fig. 3. Effect of inhibition of LRRK2 kinase activity on patient-specific cells, iPSC-differentiated neurons, primary macrophage culture on restoration of GCaase functions. The effect of inhibition of LRRK2 kinase activity on increasing the activity of acid sphingomyelinase (ASMase) and alpha-galactosidase (GLA) in iPSC-differentiated neurons of patients with GBA1-PD and galactosylceramidase (GALC) in iPSC-differentiated neurons of patients with LRRK2-PD is shown.

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