Болезнь Паркинсона, ассоциированная с мутациями в гене LRRK2: подходы к терапии

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Аннотация

Обогащенная лейциновыми повторами киназа 2 (LRRK2) относится к подсемейству тирозинкиназоподобных киназ, основной функцией которых является перенос γ-фосфата от АТР на субстрат за счет киназных доменов. Точные функции LRRK2 в клетке остаются неизвестными. Показано, что мутации в гене LRRK2, приводящие к развитию наиболее распространенной аутосомно-доминантной формы болезни Паркинсона, в основном вызывают патологическое повышение киназной активности фермента. В обзоре описана структура киназы LRRK2, ее функциональная активность в виде мономера, димера и тетрамера, а также влияние мутаций на структуру и киназную активность. Понимание строения и функций LRRK2 открывает новые перспективы для использования этой киназы в качестве терапевтической мишени при болезни Паркинсона.

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Т. С. Усенко

Петербургский институт ядерной физики им. Б. П. Константинова Научно-исследовательского центра “Курчатовский институт”; Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова

Автор, ответственный за переписку.
Email: usenko_ts@pnpi.nrcki.ru
Россия, Гатчина, 188300; Санкт-Петербург, 197022

С. Н. Пчелина

Петербургский институт ядерной физики им. Б. П. Константинова Научно-исследовательского центра “Курчатовский институт”; Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова

Email: usenko_ts@pnpi.nrcki.ru
Россия, Гатчина, 188300; Санкт-Петербург, 197022

Список литературы

  1. Jankovic J., Tan E.K. (2020) Parkinson’s disease: etiopathogenesis and treatment. J. Neurol. Neurosurg. Psychiatry. 91(8), 795–808. https://doi.org/10.1136/jnnp-2019-322338
  2. Ray Dorsey E., Elbaz A., Nichols E., Abd-Allah F., Abdelalim A., Adsuar J.C., Ansha M.G., Brayne C., Choi J.Y.J., Collado-Mateo D., Dahodwala N., Do H.P., Edessa D., Endres M., Fereshtehnejad S.M., Foreman K.J., Gankpe F.G., Gupta R., Hankey G.J., Hay S.I., Hegazy M.I., Hibstu D.T., Kasaeian A., Khader Y., Khalil I., Khang Y.H., Kim Y.J., Kokubo Y., Logroscino G., Massano J., Ibrahim N.M., Mohammed M.A., Mohammadi A., Moradi-Lakeh M., Naghavi M., Nguyen B.T., Nirayo Y.L., Ogbo F.A., Owolabi M.O., Pereira M., Postma M.J., Qorbani M., Rahman M.A., Roba K.T., Safari H., Safiri S., Satpathy M., Sawhney M., Shafieesabet A., Shiferaw M.S., Smith M., Szoeke C.E.I., Tabarés-Seisdedos R., Truong N.T., Ukwaja K.N., Venketasubramanian N., Villafaina S., Weldegwergs K.G., Westerman R., Wijeratne T., Winkler A.S., Xuan B.T., Yonemoto N., Feigin V.L., Vos T., Murray C.J.L. (2018) Global, regional, and national burden of Parkinson’s disease, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 17(11), 939–953. https://doi.org/10.1016/S1474-4422(18)30295-3
  3. Giguère N., Nanni S.B., Trudeau L.E. (2018) On cell loss and selective vulnerability of neuronal populations in Parkinson’s disease. Front. Neurol. 9, 455. https://doi.org/10.3389/fneur.2018.00455
  4. Wegrzynowicz M., Bar-On D., Calo’ L., Anichtchik O., Iovino M., Xia J., Ryazanov S., Leonov A., Giese A., Dalley J.W., Griesinger C., Ashery U., Spillantini M.G. (2019) Depopulation of dense α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model. Acta Neuropathol. 138, 575–595. https://doi.org/10.1007/s00401-019-02023-x
  5. Furukawa K., Shima A., Kambe D., Nishida A., Wada I., Sakamaki H., Yoshimura K., Terada Y., Sakato Y., Mitsuhashi M., Sawamura M., Nakanishi E., Taruno Y., Yamakado H., Fushimi Y., Okada T., Nakamoto Y., Takahashi R., Sawamoto N. (2022) Motor progression and nigrostriatal neurodegeneration in Parkinson disease. Ann. Neurol. 92. https://doi.org/10.1002/ana.26373
  6. Sagredo G.T., Tanglay O., Shahdadpuri S., Fu Y., Halliday G.M. (2024) α-Synuclein levels in Parkinson’s disease – cell types and forms that contribute to pathogenesis. Exp. Neurol. 379, 114887. https://doi.org/10.1016/j.expneurol.2024.114887
  7. Karimi-Moghadam A., Charsouei S., Bell B., Jabalameli M.R. (2018) Parkinson disease from mendelian forms to genetic susceptibility: new molecular insights into the neurodegeneration process. Cell. Mol. Neurobiol. 38(6), 1153–1178. https://doi.org/10.1007/s10571-018-0587-4
  8. Xiong Y., Dawson T.M., Dawson V.L. (2017) Models of LRRK2-associated Parkinson’s disease. Advances Neurobiol. 14, 163–191. https://doi.org/10.1007/978-3-319-49969-7_9
  9. Li D., Mastaglia F.L., Fletcher S., Wilton S.D. (2020) Progress in the molecular pathogenesis and nucleic acid therapeutics for Parkinson’s disease in the precision medicine era. Med. Res. Rev. 40(6), 2650–2681. https://doi.org/10.1002/med.21718
  10. Emelyanov A.K., Usenko T.S., Tesson C., Senkevich K.A., Nikolaev M.A., Miliukhina I.V., Kopytova A.E., Timofeeva A.A., Yakimovsky A.F., Lesage S., Brice A., Pchelina S.N. (2018) Mutation analysis of Parkinson’s disease genes in a Russian data set. Neurobiol. Aging. 71, 267.e7–267.e10. https://doi.org/10.1016/j.neurobiolaging.2018.06.027
  11. Zhang X., Kortholt A. (2023) LRRK2 structure-based activation mechanism and pathogenesis. Biomolecules. 13(4), 612. https://doi.org/10.3390/biom13040612
  12. Kumari U., Tan E.K. (2009) LRRK2 in Parkinson’s disease: genetic and clinical studies from patients. FEBS J. 276(22), 6455–6463. https://doi.org/10.1111/j.1742-4658.2009.07344.x
  13. Zimprich A., Biskup S., Leitner P., Lichtner P., Farrer M., Lincoln S., Kachergus J., Hulihan M., Uitti R.J., Calne D.B., Stoessl A.J., Pfeiffer R.F., Patenge N., Carbajal I.C., Vieregge P., Asmus F., Müller-Myhsok B., Dickson DW., Meitinger T., Strom T.M., Wszolek Z.K., Gasser T. (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 44(4), 601–607. https://doi.org/10.1016/j.neuron.2004.11.005
  14. Paisán-Ruíz C., Jain S., Evans E.W., Gilks W.P., Simón J., Van Der Brug M., De Munain A.L., Aparicio S., Gil A.M., Khan N., Johnson J., Martinez J.R., Nicholl D., Carrera I.M., Peňa A.S., De Silva R., Lees A., Martí-Massó J.F., Pérez-Tur J., Wood N.W., Singleton A.B. (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron. 44(4), 595–600. https://doi.org/10.1016/j.neuron.2004.10.023
  15. Funayama M., Hasegawa K., Kowa H., Saito M., Tsuji S., Obata F. (2002) A new locus for Parkinson’s disease (PARK8) maps to chromosome 12p11.2–q13.1. Ann. Neurol. 51(3), 296–301. https://doi.org/10.1002/ana.10113
  16. Healy D.G., Falchi M., O’Sullivan S.S., Bonifati V., Durr A., Bressman S., Brice A., Aasly J., Zabetian C.P., Goldwurm S., Ferreira J.J., Tolosa E., Kay D.M., Klein C., Williams D.R., Marras C., Lang A.E., Wszolek Z.K., Berciano J., Schapira A.H., Lynch T., Bhatia K.P., Gasser T., Lees A.J., Wood N.W. (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol. 7(7), 583–590.
  17. West A.B., Moore D.J., Biskup S., Bugayenko A., Smith W.W., Ross C.A., Dawson V.L., Dawson T.M. (2005) Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc. Natl. Acad. Sci. USA. 102(46), 16842–16847. https://doi.org/10.1073/pnas.0507360102
  18. Jaleel M., Nichols R.J., Deak M., Campbell D.G., Gillardon F., Knebel A., Alessi D.R. (2007) LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson’s disease mutants affect kinase activity. Biochem. J. 405(2), 307–317. https://doi.org/10.1042/BJ20070209
  19. Monfrini E., Di Fonzo A. (2017) Leucine-rich repeat kinase (LRRK2) genetics and Parkinson’s disease. Adv. Neurobiol. 14, 3–30. https://doi.org/10.1007/978-3-319-49969-7_1
  20. Schulte C., Gasser T. (2011) Genetic basis of Parkinson’s disease: inheritance, penetrance, and expression. Appl. Clin. Genetics. 4, 67‒80. https://doi.org/10.2147/TACG.S11639
  21. Steger M., Tonelli F., Ito G., Davies P., Trost M., Vetter M., Wachter S., Lorentzen E., Duddy G., Wilson S., Baptista M.A., Fiske B.K., Fell M.J., Morrow J.A., Reith A.D., Alessi D.R., Mann M. (2016) Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. Elife. 5, e12813. https://doi.org/10.7554/elife.12813
  22. Nguyen A.P.T., Moore D.J. (2017) Understanding the GTPase activity of LRRK2: Regulation, function, and neurotoxicity. In: Advances in Neurobiology. Springer, pp. 71–88. https://doi.org/10.1007/978-3-319-49969-7_4
  23. Kluss J.H., Mamais A., Cookson M.R. (2019) LRRK2 links genetic and sporadic Parkinson’s disease. Biochem. Soc. Trans. 47(2), 651–661. https://doi.org/10.1042/BST20180462
  24. Di Maio R., Hoffman E.K., Rocha E.M., Keeney M.T., Sanders L.H., De Miranda B.R., Zharikov A., Van Laar A., Stepan A.F., Lanz T.A., Kofler J.K., Burton E.A., Alessi D.R., Hastings T.G., Greenamyre T.J. (2018) LRRK2 activation in idiopathic Parkinson’s disease. Sci. Transl. Med. 10(451), eaar5429. https://doi.org/10.1126/scitranslmed.aar5429
  25. Ross O.A., Toft M., Whittle A.J., Johnson J.L., Papapetropoulos S., Mash D.C., Litvan I., Gordon M.F., Wszolek Z.K., Farrer M.J., Dickson D.W. (2006) Lrrk2 and Lewy body disease. Ann. Neurol. 59(2), 388‒393. https://doi.org/10.1002/ana.20731
  26. Soliman A., Cankara F.N., Kortholt A. (2020) Allosteric inhibition of LRRK2, where are we now. Biochem. Soc. Trans. 48(5), 2185–2194. https://doi.org/10.1042/BST20200424
  27. Covy J.P., Giasson B.I. (2009) Identification of compounds that inhibit the kinase activity of leucine-rich repeat kinase 2. Biochem. Biophys. Res. Commun. 378(3), 473–477. https://doi.org/10.1016/j.bbrc.2008.11.048
  28. West A.B., Moore D.J., Choi C., Andrabi S.A., Li X., Dikeman D., Biskup S., Zhang Z., Lim K.L., Dawson V.L., Dawson T.M. (2007) Parkinson’s disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum. Mol. Genet. 16(2), 223–232. https://doi.org/10.1093/hmg/ddl471
  29. Kalogeropulou A.F., Purlyte E., Tonelli F., Lange S.M., Wightman M., Prescott A.R., Padmanabhan S., Sammler E., Alessi D.R. (2022) Impact of 100 LRRK2 variants linked to Parkinson’s disease on kinase activity and microtubule binding. Biochem. J. 479(17), 1759–1783. https://doi.org/10.1042/BCJ20220161
  30. Daniẽls V., Vancraenenbroeck R., Law B.M.H., Greggio E., Lobbestael E., Gao F., De Maeyer M., Cookson M.R., Harvey K., Baekelandt V., Taymans J.M. (2011) Insight into the mode of action of the LRRK2 Y1699C pathogenic mutant. J. Neurochem. 116(2), 304–315. https://doi.org/10.1111/j.1471-4159.2010.07105.x
  31. Gloeckner C.J., Kinkl N., Schumacher A., Braun R.J., O’Neill E., Meitinger T., Kolch W., Prokisch H., Ueffing M. (2006) The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum. Mol. Genet. 15(2), 223–232. https://doi.org/10.1093/hmg/ddi439
  32. Puschmann A., Englund E., Ross O.A., Vilariño-Güell C., Lincoln S.J., Kachergus J.M., Cobb S.A., Törnqvist A.L., Rehncrona S., Widner H., Wszolek Z.K., Farrer M.J., Nilsson C. (2012) First neuropathological description of a patient with Parkinson’s disease and LRRK2 p.N1437H mutation. Parkinsonism Relat. Disord. 18(4), 332–338. https://doi.org/10.1016/j.parkreldis.2011.11.019
  33. Aasly J.O., Vilariño-Güell C., Dachsel J.C., Webber P.J., West A.B., Haugarvoll K., Johansen K.K., Toft M., Nutt J.G., Payami H., Kachergus J.M., Lincoln S.J., Felic A., Wider C., Soto-Ortolaza A.I., Cobb S.A., White L.R., Ross O.A., Farrer M.J. (2010) Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson’s disease. Mov. Disord. 25(13), 2156–2163. https://doi.org/10.1002/mds.23265
  34. Tan E.K., Tan L.C., Lim H.Q., Li R., Tang M., Yih Y., Pavanni R., Prakash K.M., Fook-Chong S., Zhao Y. (2008) LRRK2 R1628P increases risk of Parkinson’s disease: replication evidence. Hum. Genet. 124(3), 287–288. https://doi.org/10.1007/s00439-008-0544-2
  35. Shu Y., Ming J., Zhang P., Wang Q., Jiao F., Tian B. (2016) Parkinson-related LRRK2 mutation R1628P enables Cdk5 phosphorylation of LRRK2 and upregulates its kinase activity. PLoS One. 11(3), e0149739. https://doi.org/10.1371/journal.pone.0149739
  36. Tezuka T., Taniguchi D., Sano M., Shimada T., Oji Y., Tsunemi T., Ikeda A., Li Y., Yoshino H., Ogata J., Shiba-Fukushima K., Funayama M., Nishioka K., Imai Y., Hattori N. (2022) Pathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson’s disease. NPJ Parkinsons Dis. 8, 97. https://doi.org/10.1038/s41531-022-00367-y
  37. Rudenko I.N., Kaganovich A., Hauser D.N., Beylina A., Chia R., Ding J., Maric D., Jaffe H., Cookson M.R. (2012) The G2385R variant of leucine-rich repeat kinase 2 associated with Parkinson’s disease is a partial loss-of-function mutation. Biochem. J. 446(1), 99–111. https://doi.org/10.1042/BJ20120637
  38. Mills R.D., Liang L.Y., Lio D.S.S., Mok Y.F., Mulhern T.D., Cao G., Griffin M., Kenche V.B., Culvenor J.G., Cheng H.C. (2018) The Roc-COR tandem domain of leucine-rich repeat kinase 2 forms dimers and exhibits conventional Ras-like GTPase properties. J. Neurochem. 147(3), 409–428. https://doi.org/10.1111/jnc.14566
  39. Mills R.D., Mulhern T.D., Cheng H.C., Culvenor J.G. (2012) Analysis of LRRK2 accessory repeat domains: prediction of repeat length, number and sites of Parkinson’s disease mutations. Biochem. Soc. Trans. 40(5), 1086–1089. https://doi.org/10.1042/BST20120088
  40. Deng J., Lewis P.A., Greggio E., Sluch E., Beilina A., Cookson M.R. (2008) Structure of the ROC domain from the Parkinson’s disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase. Proc. Natl. Acad. Sci. USA. 105(5), 1499–1504. https://doi.org/10.1073/pnas.0709098105
  41. Terheyden S., Ho F.Y., Gilsba B.K., Wittinghofer A., Kortholt A. (2015) Revisiting the Roco G-protein cycle. Biochem. J. 465(1), 139–147. https://doi.org/10.1042/BJ20141095
  42. Gilsbach B.K., Ho F.Y., Vetter I.R., Van Haastert P.J.M., Wittinghofer A., Kortholt A. (2012) Roco kinase structures give insights into the mechanism of Parkinson disease-related leucine-rich-repeat kinase 2 mutations. Proc. Natl. Acad. Sci. USA. 109(26), 10322–10327. https://doi.org/10.1073/pnas.1203223109
  43. Gotthardt K., Weyand M., Kortholt A., Van Haastert P.J.M., Wittinghofer A. (2008) Structure of the Roc-COR domain tandem of C. tepidum, a prokaryotic homologue of the human LRRK2 Parkinson kinase. EMBO J. 27(16), 2239–2249. https://doi.org/10.1038/emboj.2008.150
  44. Sejwal K., Chami M., Rémigy H., Vancraenenbroeck R., Sibran W., Sütterlin R., Baumgartner P., McLeod R., Chartier-Harlin M.C., Baekelandt V., Stahlberg H., Taymans J.M. (2017) Cryo-EM analysis of homodimeric full-length LRRK2 and LRRK1 protein complexes. Sci. Rep. 7, 8667. https://doi.org/10.1038/s41598-017-09126-z
  45. Guaitoli G., Raimondi F., Gilsbach B.K., Gómez-Llorente Y., Deyaert E., Renzi F., Li X., Schaffner A., Jagtap P.K.A., Boldt K., Von Zweydorf F., Gotthardt K., Lorimer D.D., Yue Z., Burgin A., Janjic N., Sattler M., Versées W., Ueffing M., Ubarretxena-Belandia I., Kortholt A., Gloeckner C.J. (2016) Structural model of the dimeric Parkinson’s protein LRRK2 reveals a compact architecture involving distant interdomain contacts. Proc. Natl. Acad. Sci. USA. 113(30), E4357‒4366. https://doi.org/10.1073/pnas.1523708113
  46. Myasnikov A., Zhu H., Hixson P., Xie B., Yu K., Pitre A., Peng J., Sun J. (2021) Structural analysis of the full-length human LRRK2. Cell. 184(13), 3519‒3527.e10. https://doi.org/10.1016/j.cell.2021.05.004
  47. Deniston C.K., Salogiannis J., Mathea S., Snead D.M., Lahiri I., Matyszewski M., Donosa O., Watanabe R., Böhning J., Shiau A.K., Knapp S., Villa E., Reck-Peterson S.L., Leschziner A.E. (2020) Structure of LRRK2 in Parkinson’s disease and model for microtubule interaction. Nature. 588(7837), 344–349. https://doi.org/10.1038/s41586-020-2673-2
  48. Snead D.M., Matyszewski M., Dickey A.M., Lin Y.X., Leschziner A.E., Reck-Peterson S.L. (2022) Structural basis for Parkinson’s disease-linked LRRK2’s binding to microtubules. Nat. Struct. Mol. Biol. 29(12), 1196–1207. https://doi.org/10.1038/s41594-022-00863-y
  49. Watanabe R., Buschauer R., Böhning J., Audagnotto M., Lasker K., Lu T.W., Boassa D., Taylor S., Villa E. (2020) The in situ structure of Parkinson’s disease-linked LRRK2. Cell. 182(6), 1508–1518.e16. https://doi.org/10.1016/j.cell.2020.08.004
  50. Kett L.R., Boassa D., Ho C.C.Y., Rideout H.J., Hu J., Terada M., Ellisman M., Dauer W.T. (2012) LRRK2 Parkinson disease mutations enhance its microtubule association. Hum. Mol. Genet. 21(4), 890–899. https://doi.org/10.1093/hmg/ddr526
  51. Schmidt S.H., Weng J.H., Aoto P.C., Boassa D., Mathea S., Silletti S., Hu J., Wallbott M., Komives E.A., Knapp S., Herberg F.W., Taylor S.S. (2021) Conformation and dynamics of the kinase domain drive subcellular location and activation of LRRK2. Proc. Natl. Acad. Sci. USA. 118(23), e2100844118. https://doi.org/10.1073/PNAS.2100844118
  52. Webber P.J., Smith A.D., Sen S., Renfrow M.B., Mobley J.A., West A.B. (2011) Autophosphorylation in the leucine-rich repeat kinase 2 (LRRK2) GTPase domain modifies kinase and GTP-binding activities. J. Mol. Biol. 412(1), 94–110. https://doi.org/10.1016/j.jmb.2011.07.033
  53. Liu Z., Mobley J.A., DeLucas L.J., Kahn R.A., West A.B. (2016) LRRK2 autophosphorylation enhances its GTPase activity. FASEB J. 30(1), 336–347. https://doi.org/10.1096/fj.15-277095
  54. Zhu H., Tonelli F., Turk M., Prescott A., Alessi D.R., Sun J. (2023) Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2. Science. 382(6677), 1404–1411. https://doi.org/10.1126/science.adi9926
  55. Manschwetus J.T., Wallbott M., Fachinger A., Obergruber C., Pautz S., Bertinetti D., Schmidt S.H., Herberg F.W. (2020) Binding of the human 14–3–3 isoforms to distinct sites in the leucine-rich repeat kinase 2. Front. Neurosci. 14, 32. https://doi.org/10.3389/fnins.2020.00302
  56. Manzoni C., Mamais A., Dihanich S., Abeti R., Soutar M.P.M., Plun-Favreau H., Giunti P., Tooze S.A., Bandopadhyay R., Lewis P.A. (2013) Inhibition of LRRK2 kinase activity stimulates macroautophagy. Biochim. Biophys. Acta Mol. Cell Res. 1833(12), 2900–2910. https://doi.org/10.1016/j.bbamcr.2013.07.020
  57. Fonseca-Ornelas L., Stricker J.M.S., Soriano-Cruz S., Weykopf B., Dettmer U., Muratore C.R., Scherzer C.R., Selkoe D.J. (2022) Parkinson-causing mutations in LRRK2 impair the physiological tetramerization of endogenous α-synuclein in human neurons. NPJ Parkinsons Dis. 8(1), 118. https://doi.org/10.1038/s41531-022-00380-1
  58. Vides E.G., Adhikari A., Chiang C.Y., Lis P., Purlyte E., Limouse C., Shumate J.L., Spínola-Lasso E., Dhekne H.S., Alessi D.R., Pfeffer S.R. (2022) A feed-forward pathway drives LRRK2 kinase membrane recruitment and activation. Elife. 11, e79771. https://doi.org/10.7554/eLife.79771
  59. Berger Z., Smith K.A., Lavoie M.J. (2010) Membrane localization of LRRK2 is associated with increased formation of the highly active LRRK2 dimer and changes in its phosphorylation. Biochemistry. 49(26), 5511–5523. https://doi.org/10.1021/bi100157u
  60. Liu Z., Bryant N., Kumaran R., Beilina A., Abeliovich A., Cookson M.R., West A.B. (2018) LRRK2 phosphorylates membrane-bound Rabs and is activated by GTP-bound Rab7L1 to promote recruitment to the trans-Golgi network. Hum. Mol. Genet. 27(2), 385–395. https://doi.org/10.1093/hmg/ddx410
  61. Dzamko N., Inesta-Vaquera F., Zhang J., Xie C., Cai H., Arthur S., Tan L., Choi H., Gray N., Cohen P., Pedrioli P., Clark K., Alessi D.R. (2012) The IkappaB kinase family phosphorylates the Parkinson’s disease kinase LRRK2 at Ser935 and Ser910 during Toll-like receptor signaling. PLoS One. 7(6), e39132. https://doi.org/10.1371/journal.pone.0039132
  62. Sheng Z., Zhang S., Bustos D., Kleinheinz T., Le Pichon C.E., Dominguez S.L., Solanoy H.O., Drummond J., Zhang X., Ding X., Cai F., Song Q., Li X., Yue Z., van der Brug M.P., Burdick D.J., Gunzner-Toste J., Chen H., Liu X., Estrada A.A., Sweeney Z.K., Scearce-Levie K., Moffat J.G., Kirkpatrick D.S., Zhu H. (2012) Ser1292 autophosphorylation is an indicator of LRRK2 kinase activity and contributes to the cellular effects of PD mutations. Sci. Transl. Med. 4(164), 164ra161. https://doi.org/10.1126/scitranslmed.3004485
  63. Marchand A., Drouyer M., Sarchione A., Chartier-Harlin M.C., Taymans J.M. (2020) LRRK2 phosphorylation, more than an epiphenomenon. Front. Neurosci. 14, 527. https://doi.org/10.3389/fnins.2020.00527
  64. Lavalley N.J., Slone S.R., Ding H., West A.B., Yacoubian T.A. (2016) 14–3–3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening. Hum. Mol. Genet. 25(1), 109–122. https://doi.org/10.1093/hmg/ddv453
  65. Ysselstein D., Nguyen M., Young T.J., Severino A., Schwake M., Merchant K., Krainc D. (2019) LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson’s disease patients. Nat. Commun. 10(1), 5570. https://doi.org/10.1038/s41467-019-13413-w
  66. Усенко Т.С., Башарова К.С., Безрукова А.И., Николаев М.А., Милюхина И.В., Байдакова Г.В., Захарова Е.Ю., Пчелина С.Н. (2022) Селективное ингибирование киназной активности LRRK2 как подход к терапии болезни Паркинсона. Мед. генетика. 21(12), 26–29. https://doi.org/10.25557/2073-7998.2022.12.26-2
  67. Sanyal A., Novis H.S., Gasser E., Lin S., LaVoie M.J. (2020) LRRK2 kinase inhibition rescues deficits in lysosome function due to heterozygous GBA1 expression in human iPSC-derived neurons. Front. Neurosci. 14, 442. https://doi.org/10.3389/fnins.2020.00442
  68. Kedariti M., Frattini E., Baden P., Cogo S., Civiero L., Ziviani E., Zilio G., Bertoli F., Aureli M., Kaganovich A., Cookson M.R., Stefanis L., Surface M., Deleidi M., Di Fonzo A., Alcalay R.N., Rideout H., Greggio E., Plotegher N. (2022) LRRK2 kinase activity regulates GCase level and enzymatic activity differently depending on cell type in Parkinson’s disease. NPJ Parkinsons Dis. 8, 92. https://doi.org/10.1038/s41531-022-00354-3
  69. Bae E.J., Kim D.K., Kim C., Mante M., Adame A., Rockenstein E., Ulusoy A., Klinkenberg M., Jeong G.R., Bae J.R., Lee C., Lee H.J., Lee B.D., Di Monte D.A., Masliah E., Lee S.J. (2018) LRRK2 kinase regulates α-synuclein propagation via RAB35 phosphorylation. Nat. Commun. 9(1), 3465. https://doi.org/10.1038/s41467-018-05958-z
  70. Yin G., Lopes da Fonseca T., Eisbach S.E., Anduaga A.M., Breda C., Orcellet M.L., Szegő É.M., Guerreiro P., Lázaro D.F., Braus G.H., Fernandez C.O., Griesinger C., Becker S., Goody R.S., Itzen A., Giorgini F., Outeiro T.F., Zweckstetter M. (2014) α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner. Neurobiol Dis. 70, 149‒161. https://doi.org/10.1016/j.nbd.2014.06.018
  71. Teixeira M., Sheta R., Idi W., Oueslati A. (2021) Alpha-synuclein and the endolysosomal system in Parkinson’s disease: guilty by association. Biomolecules. 11(9), 1333. https://doi.org/10.3390/biom11091333
  72. Inoshita T., Arano T., Hosaka Y., Meng H., Umezaki Y., Kosugi S., Morimoto T., Koike M., Chang H.Y., Imai Y., Hattori N. (2017) Vps35 in cooperation with LRRK2 regulates synaptic vesicle endocytosis through the endosomal pathway in Drosophila. Hum. Mol. Genet. 26(15), 2933–2948. https://doi.org/10.1093/hmg/ddx179
  73. Taylor M., Alessi D.R. (2020) Advances in elucidating the function of leucine-rich repeat protein kinase-2 in normal cells and Parkinson’s disease. Curr. Opin. Cell Biol. 63, 102–113. https://doi.org/10.1016/j.ceb.2020.01.001
  74. Khan S.S., Sobu Y., Dhekne H.S., Tonelli F., Berndsen K., Alessi D.R., Pfeffer S.R. (2021) Pathogenic lrrk2 control of primary cilia and hedgehog signaling in neurons and astrocytes of mouse brain. Elife. 10, e67900. https://doi.org/10.7554/eLife.67900
  75. Wang X., Yan M.H., Fujioka H., Liu J., Wilson-delfosse A., Chen S.G., Perry G., Casadesus G., Zhu X. (2012) LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1. Hum. Mol. Genet. 21(9), 1931–1944. https://doi.org/10.1093/hmg/dds003
  76. Kalogeropulou A.F., Zhao J., Bolliger M.F., Memou A., Narasimha S., Molitor T.P., Wilson W.H., Rideout H.J., Nichols J.R. (2018) P62/SQSTM1 is a novel leucine-rich repeat kinase 2 (LRRK2) substrate that enhances neuronal toxicity. Biochem. J. 475(7), 1271–1293. https://doi.org/10.1042/BCJ20170699
  77. Liu W.J., Ye L., Huang W.F., Guo L.J., Xu Z.G., Wu H.L., Yang C., Liu H.F. (2016) p62 links the autophagy pathway and the ubiqutin-proteasome system upon ubiquitinated protein degradation. Cell Mol. Biol. Lett. 21, 29. https://doi.org/10.1186/s11658-016-0031-z
  78. Su J., Liu F., Xia M., Xu Y., Li X., Kang J., Li Y., Sun L. (2015) p62 participates in the inhibition of NF-κB signaling and apoptosis induced by sulfasalazine in human glioma U251 cells. Oncol. Rep. 34(1), 235‒243. https://doi.org/10.3892/or.2015.3944
  79. Matsumoto G., Wada K., Okuno M., Kurosawa M., Nukina N. (2011) Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol. Cell. 44(2), 279‒289. https://doi.org/10.1016/j.molcel.2011.07.039
  80. Deng Z., Lim J., Wang Q., Purtell K., Wu S., Palomo G.M., Tan H., Manfredi G., Zhao Y., Peng J., Hu B., Chen S., Yue Z. (2020) ALS-FTLD-linked mutations of SQSTM1/p62 disrupt selective autophagy and NFE2L2/NRF2 anti-oxidative stress pathway. Autophagy. 16(5), 917–931. https://doi.org/10.1080/15548627.2019.1644076
  81. Hennig P., Fenini G., Filippo M., Di Karakaya T., Beer H.D. (2021) The pathways underlying the multiple roles of p62 in inflammation and cancer. Biomedicines. 9(7), 707. https://doi.org/10.3390/biomedicines9070707
  82. Pérez-Carrión M.D., Posadas I., Solera J., Ceña V. (2022) LRRK2 and proteostasis in Parkinson’s disease. Int. J. Mol. Sci. 23(12), 6808. https://doi.org/10.3390/ijms23126808
  83. Gillardon F. (2009) Leucine-rich repeat kinase 2 phosphorylates brain tubulin-beta isoforms and modulates microtubule stability — a point of convergence in Parkinsonian neurodegeneration? J. Neurochem. 110(5), 1514–1522. https://doi.org/10.1111/j.1471-4159.2009.06235.x
  84. Imai Y., Gehrke S., Wang H.Q., Takahashi R., Hasegawa K., Oota E., Lu B. (2008) Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. EMBO J. 27(18), 2432–2443. https://doi.org/10.1038/emboj.2008.163
  85. Krumova P., Reyniers L., Meyer M., Lobbestael E., Stauffer D., Gerrits B., Muller L., Hoving S., Kaupmann K., Voshol J., Fabbro D., Bauer A., Rovelli G., Taymans J.M., Bouwmeester T., Baekelandt V. (2015) Chemical genetic approach identifies microtubule affinity-regulating kinase 1 as a leucine-rich repeat kinase 2 substrate. FASEB J. 29(7), 2980–2992. https://doi.org/10.1096/fj.14-262329
  86. Matta S., Van Kolen K., da Cunha R., van den Bogaart G., Mandemakers W., Miskiewicz K., De Bock P.J., Morais V.A., Vilain S., Haddad D., Delbroek L., Swerts J., Chávez-Gutiérrez L., Esposito G., Daneels G., Karran E., Holt M., Gevaert K., Moechars D.W., De Strooper B., Verstreken P. (2012) LRRK2 controls an endoA phosphorylation cycle in synaptic endocytosis. Neuron. 75(6), 1008–1021. https://doi.org/10.1016/j.neuron.2012.08.022
  87. Islam M.S., Nolte H., Jacob W., Ziegler A.B., Pütz S., Grosjean Y., Szczepanowska K., Trifunovic A., Braun T., Heumann H., Heumann R., Hovemann B., Moore D.J., Krüger M. (2016) Human R1441C LRRK2 regulates the synaptic vesicle proteome and phosphoproteome in a Drosophila model of Parkinson’s disease. Hum. Mol. Genet. 25(24), 5365–5382. https://doi.org/10.1093/hmg/ddw352
  88. Kawakami F., Yabata T., Ohta E., Maekawa T., Shimada N., Suzuki M., Maruyama H., Ichikawa T., Obata F. (2012) LRRK2 phosphorylates tubulin-associated tau but not the free molecule: LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth. PLoS One. 7(1), e30834. https://doi.org/10.1371/journal.pone.0030834
  89. Kanao T., Venderova K., Park D.S., Unterman T., Lu B., Imai Y. (2010) Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila. Hum. Mol. Genet. 19(19), 3747–3758. https://doi.org/10.1093/hmg/ddq289
  90. Yun H.J., Park J., Ho D.H., Kim H., Kim C.H., Oh H., Ga I., Seo H., Chang S., Son I., Seol W. (2013) LRRK2 phosphorylates Snapin and inhibits interaction of Snapin with SNAP-25. Exp. Mol. Med. 45(8), e36. https://doi.org/10.1038/emm.2013.68
  91. Martin I., Kim J.W., Lee B.D., Kang H.C., Xu J.C., Jia H., Stankowski J., Kim M.S., Zhong J., Kumar M., Andrabi S.A., Xiong Y., Dickson D.W., Wszolek Z.K., Pandey A., Dawson T.M., Dawson V.L. (2014) Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson’s disease. Cell. 157(2), 472–485. https://doi.org/10.1016/j.cell.2014.01.064
  92. Dhekne H.S., Yanatori I., Gomez R.C., Tonelli F., Diez F., Schüle B., Steger M., Alessi D.R., Pfeffer S.R. (2018) A pathway for Parkinson’s disease LRRK2 kinase to block primary cilia and sonic hedgehog signaling in the brain. Elife. 7, e40202. https://doi.org/10.7554/eLife.40202
  93. Rivero-Ríos P., Romo-Lozano M., Madero-Pérez J., Thomas A.P., Biosa A., Greggio E., Hilfiker S. (2019) The G2019S variant of leucine-rich repeat kinase 2 (LRRK2) alters endolysosomal trafficking by impairing the function of the GTPase RAB8A. J. Biol. Chem. 294(13), 4738–4758. https://doi.org/10.1074/jbc.RA118.005008
  94. Yue M., Hinkle K.M., Davies P., Trushina E., Fiesel F.C., Christenson T.A., Schroeder A.S., Zhang L., Bowles E., Behrouz B., Lincoln S.J., Beevers J.E., Milnerwood A.J., Kurti A., McLean P.J., Fryer J.D., Springer W., Dickson D.W., Farrer M.J., Melrose H.L. (2015) Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice. Neurobiol. Dis. 78, 172–195. https://doi.org/10.1016/j.nbd.2015.02.031
  95. Madureira M., Connor-Robson N., Wade-Martins R. (2020) “LRRK2: autophagy and lysosomal activity”. Front. Neurosci. 14, 498. https://doi.org/10.3389/fnins.2020.00498
  96. Orenstein S.J., Kuo S.H., Tasset I., Arias E., Koga H., Fernandez-Carasa I., Cortes E., Honig L.S., Dauer W., Consiglio A., Raya A., Sulzer D., Cuervo A.M. (2013) Interplay of LRRK2 with chaperone-mediated autophagy. Nat. Neurosci. 16(4), 394–406. https://doi.org/10.1038/nn.3350
  97. Jia H., Liang Z., Zhang X., Wang J., Xu W., Qian H. (2017) 14–3–3 proteins: an important regulator of autophagy in diseases. Am.J. Transl. Res. 9(11), 4738–4746.
  98. Stark C., Breitkreutz B.J., Reguly T., Boucher L., Breitkreutz A., Tyers M. (2006) BioGRID: a general repository for interaction datasets. Nucl. Acids Res. 34, D535–539. https://doi.org/10.1093/nar/gkj109
  99. Alessi D.R., Sammler E. (2018) LRRK2 kinase in Parkinson’s disease. Science. 360(6384), 36–37. https://doi.org/10.1126/science.aar5683
  100. Naskar A., Bhanja K.K., Roy R.K., Patra N. (2023) Role of the residue Q1919 in increasing kinase activity of G2019S LRRK2 kinase: a computational study. ChemPhysChem. 24(21), e202300306. https://doi.org/10.1002/cphc.202300306
  101. Weng J.H., Aoto P.C., Lorenz R., Wu J., Schmidt S.H., Manschwetus J.T., Kaila-Sharma P., Silletti S., Mathea S., Chatterjee D., Knapp S., Herberg F.W., Taylor S.S. (2022) LRRK2 dynamics analysis identifies allosteric control of the crosstalk between its catalytic domains. PLoS Biol. 20(2), e3001427. https://doi.org/10.1371/journal.pbio.3001427
  102. Hui K.Y., Fernandez-Hernandez H., Hu J., Schaffner A., Pankratz N., Hsu N.Y., Chuang L.S., Carmi S., Villaverde N., Li X., Rivas M., Levine A.P., Bao X., Labrias P.R., Haritunians T., Ruane D., Gettler K., Chen E., Li D., Schiff E.R., Pontikos N., Barzilai N., Brant S.R., Bressman S., Cheifetz A.S., Clark L.N., Daly M.J., Desnick R.J., Duerr R.H., Katz S., Lencz T., Myers R.H., Ostrer H., Ozelius L., Payami H., Peter Y., Rioux J.D., Segal A.W., Scott W.K., Silverberg M.S., Vance J.M., Ubarretxena-Belandia I., Foroud T., Atzmon G., Pe’er I., Ioannou Y., McGovern D.P.B., Yue Z., Schadt E.E., Cho J.H., Peter I. (2018) Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease. Sci. Transl. Med. 10(423), eaai7795. https://doi.org/10.1126/scitranslmed.aai7795
  103. Fraser K.B., Moehle M.S., Daher J.P.L., Webber P.J., Williams J.Y., Stewart C.A., Yacoubian T.A., Cowell R.M., Dokland T., Ye T., Chen D., Siegal G.P., Galemmo R.A., Tsika E., Moore D.J., Standaert D.G., Kojima K., Mobley J.A., West A.B. (2013) LRRK2 secretion in exosomes is regulated by 14-3-3. Hum. Mol. Genet. 22(24), 4988–5000. https://doi.org/10.1093/hmg/ddt346
  104. Zhang P., Fan Y., Ru H., Wang L., Magupalli V.G., Taylor S.S., Alessi D.R., Wu H. (2019) Crystal structure of the WD40 domain dimer of LRRK2. Proc. Natl. Acad. Sci. USA. 116(5), 1579–1584. https://doi.org/10.1073/pnas.1817889116
  105. Wojewska D.N., Kortholt A. (2021) Lrrk2 targeting strategies as potential treatment of Parkinson’s disease. Biomolecules. 11(8), 1101. https://doi.org/10.3390/biom11081101
  106. Deng X., Dzamko N., Prescott A., Davies P., Liu Q., Yang Q., Lee J.D., Patricelli M.P., Nomanbhoy T.K., Alessi D.R., Gray N.S. (2011) Characterization of a selective inhibitor of the Parkinson’s disease kinase LRRK2. Nat. Chem. Biol. 7(4), 203–205. https://doi.org/10.1038/nchembio.538
  107. Reith A.D., Bamborough P., Jandu K., Andreotti D., Mensah L., Dossang P., Choi H.G., Deng X., Zhang J., Alessi D.R., Gray N.S. (2012) GSK2578215A; a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor. Bioorg. Med. Chem. Lett. 22(17), 5625–5629. https://doi.org/10.1016/j.bmcl.2012.06.104
  108. Estrada A.A., Liu X., Baker-Glenn C., Beresford A., Burdick D.J., Chambers M., Chan B.K., Chen H., Ding X., Dipasquale A.G., Dominguez S.L., Dotson J., Drummond J., Flagella M, Flynn S., Fuji R., Gill A., Gunzner-Toste J., Harris S.F., Heffron T.P., Kleinheinz T., Lee D.W., Le Pichon C.E., Lyssikatos J.P., Medhurst A.D., Moffat J.G., Mukund S., Nash K., Scearce-Levie K., Sheng Z., Shore D.G., Tran T., Trivedi N., Wang S., Zhang S., Zhang X., Zhao G., Zhu H., Sweeney Z.K. (2012) Discovery of highly potent, selective, and brain-penetrable leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. J. Med. Chem. 55 (22), 9416–9433. https://doi.org/10.1021/jm301020q
  109. Henderson J.L., Kormos B.L., Hayward M.M., Coffman K.J., Jasti J., Kurumbail R.G., Wager T.T., Verhoest P.R., Noell G.S., Chen Y., Needle E., Berger Z., Steyn S.J., Houle C., Hirst W.D., Galatsis P. (2015) Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor. J. Med. Chem. 58(1). https://doi.org/10.1021/jm5014055
  110. Baptista M.A.S., Merchant K., Barrett T., Bhargava S., Bryce D.K., Michael Ellis J., Estrada A.A., Fell M.J., Fiske B.K., Fuji R.N., Galatsis P., Henry A.G., Hill S., Hirst W., Houle C., Kennedy M.E., Liu X., Maddess M.L., Markgraf C., Mei H., Meier W.A., Needle E., Ploch S., Royer C., Rudolph K., Sharma A.K., Stepan A., Steyn S., Trost C., Yin Z., Yu H., Wang X., Sherer T.B. (2020) LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits. Sci. Transl. Med. 12(540), eaav0820. https://doi.org/10.1126/scitranslmed.aav0820
  111. Fell M.J., Mirescu C., Basu K., Cheewatrakoolpong B., DeMong D.E., Ellis J.M., Hyde L.A., Lin Y., Markgraf C.G., Mei H., Miller M., Poulet F.M., Scott J.D., Smith M.D., Yin Z., Zhou X, Parker E.M., Kennedy M.E., Morrow J.A. (2015) MLi-2, a potent, selective, and centrally active compound for exploring the therapeutic potential and safety of LRRK2 kinase inhibition. J. Pharmacol. Exp. Ther. 355(3), 397–409. https://doi.org/10.1124/jpet.115.227587
  112. Jennings D., Huntwork-Rodriguez S., Henry A.G., Sasaki J.C., Meisner R., Diaz D., Solanoy H., Wang X., Negrou E., Bondar V.V., Ghosh R., Maloney M.T., Propson N.E., Zhu Y., Maciuca R.D., Harris L., Kay A., LeWitt P., King T.A., Kern D., Ellenbogen A., Goodman I., Siderowf A., Aldred J., Omidvar O., Masoud S.T., Davis S.S., Arguello A., Estrada A.A., de Vicente J., Sweeney Z.K., Astarita G., Borin M.T., Wong B.K., Wong H., Nguyen H., Scearce-Levie K., Ho C., Troyer M.D. (2022) Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson’s disease. Sci. Transl. Med. 14(648), eabj2658. https://doi.org/10.1126/scitranslmed.abj2658
  113. Zhao H.T., John N., Delic V., Ikeda-Lee K., Kim A., Weihofen A., Swayze E.E., Kordasiewicz H.B., West A.B., Volpicelli-Daley L.A. (2017) LRRK2 antisense oligonucleotides ameliorate α-synuclein inclusion formation in a Parkinson’s disease mouse model. Mol. Ther. Nucl. Acids. 8, 508–519. https://doi.org/10.1016/j.omtn.2017.08.002
  114. Korecka J.A., Thomas R., Hinrich A.J., Moskites A.M., Macbain Z.K., Hallett P.J., Isacson O., Hastings M.L. (2021) Splice-switching antisense oligonucleotides reduce LRRK2 kinase activity in human LRRK2 transgenic mice. Mol. Ther. Nucl. Acids. 21, 623–635. https://doi.org/10.1016/j.omtn.2020.06.027
  115. Taymans J.M., Fell M., Greenamyre T., Hirst W.D., Mamais A., Padmanabhan S., Peter I., Rideout H., Thaler A. (2023) Perspective on the current state of the LRRK2 field. NPJ Parkinsons Dis. 9(1), 104. https://doi.org/10.1038/s41531-023-00544-7
  116. Gündner A.L., Duran-Pacheco G., Zimmermann S., Ruf I., Moors T., Baumann K., Jagasia R., van de Berg W.D.J., Kremer T. (2019) Path mediation analysis reveals GBA impacts Lewy body disease status by increasing α-synuclein levels. Neurobiol. Dis. 121, 205–213. https://doi.org/10.1016/j.nbd.2018.09.015
  117. Navarro-Romero A., Fernandez-Gonzalez I., Riera J, Montpeyo M., Albert-Bayo M., Lopez-Royo T., Castillo-Sanchez P., Carnicer-Caceres C., Arranz-Amo J.A., Castillo-Ribelles L., Pradas E., Casas J., Vila M., Martinez-Vicente M. (2022) Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology. NPJ Parkinsons Dis. 8(1), 126. https://doi.org/10.1038/s41531-022-00397-6
  118. Yang W., Li X., Yin N. (2020) Increased α-synuclein oligomerization is associated with decreased activity of glucocerebrosidase in the aging human striatum and hippocampus. Neurosci. Lett. 733, 135093. https://doi.org/10.1016/j.neulet.2020.135093
  119. Mullin S., Smith L., Lee K., D’Souza G., Woodgate P., Elflein J., Hällqvist J., Toffoli M., Streeter A., Hosking J., Heywood W.E., Khengar R., Campbell P., Hehir J., Cable S., Mills K., Zetterberg H., Limousin P., Libri V., Foltynie T., Schapira A.H.V. (2020) Ambroxol for the treatment of patients with Parkinson disease with and without glucocerebrosidase gene mutations: a nonrandomized, noncontrolled trial. JAMA Neurol. 77(4), 427‒434.
  120. Kopytova A.E., Rychkov G.N., Nikolaev M.A., Baydakova G.V., Cheblokov A.A., Senkevich K.A., Bogdanova D.A., Bolshakova O.I., Miliukhina I.V., Bezrukikh V.A., Salogub G.N., Sarantseva S.V., Usenko T.C., Zakharova E.Y., Emelyanov A.K., Pchelina S.N. (2021) Ambroxol increases glucocerebrosidase (GCase) activity and restores GCase translocation in primary patient-derived macrophages in Gaucher disease and Parkinsonism. Parkinsonism Relat. Disord. 84, 112–121. https://doi.org/10.1016/j.parkreldis.2021.02.003
  121. Senkevich K.A., Kopytova A.E., Usenko T.S., Emelyanov A.K., Pchelina S.N. (2021) Parkinson’s disease associated with GBA gene mutations: molecular aspects and potential treatment approaches. Acta Naturae. 13(2), 70–78. https://doi.org/10.32607/actanaturae.11031
  122. Ramírez M.B., Ordóñez A.J.L., Fdez E., Madero-Pérez J., Gonnelli A., Drouyer M., Chartier-Harlin M.C., Taymans J.M., Bubacco L., Greggio E., Hilfiker S. (2017) GTP binding regulates cellular localization of Parkinson’s disease-associated LRRK2. Hum. Mol. Genet. 26(14), 2747–2767. https://doi.org/10.1093/hmg/ddx161
  123. Araki M., Ito G., Tomita T. (2018) Physiological and pathological functions of LRRK2: implications from substrate proteins. Neuronal. Signal. 2(4), NS20180005. https://doi.org/10.1042/NS20180005
  124. Ho P.W.L., Chang E.E.S., Leung C.T., Liu H., Malki Y., Pang S.Y.Y., Choi Z.Y.K., Liang Y., Lai W.S., Ruan Y., Leung K.M.Y., Yung S., Mak J.C.W., Kung M.H.W., Ramsden D.B., Ho S.L. (2022) Long-term inhibition of mutant LRRK2 hyper-kinase activity reduced mouse brain α-synuclein oligomers without adverse effects. NPJ Parkinsons Dis. 8(1), 115. https://doi.org/10.1038/s41531-022-00386-9

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2. Рис. 1. Схематическое представление LRRK2 с обозначением функциональных доменов и расположения наиболее распространенных мутаций и вариантов риска (*) БП. Домены LRRK2: ARM (armadillo), анкирин (ANK), богатые лейцином повторы (LRR), Ras-подобная GTPаза (домен Ras-of-complex (ROC)), киназа, каркасный домен (С-конец ROC (COR)) и WD40 [26] (Creative Commons Attribution License 4.0, с изменениями).

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3. Рис. 2. Схема механизма активации LRRK2 через Rab29. LRRK2 в основном присутствует в цитозоле в мономерной GTP-связанной форме, способной образовывать стабильный комплекс с белками 14-3-3. Связывание LRRK2 c Rab29 индуцирует мембранную локализацию LRRK2. На мембране GTP гидролизуется, LRRK2 димеризуется, что приводит к активации киназного домена LRRK2 и инициации фосфорилирования субстратов. Низкое сродство LRRK2 к GTP способствует быстрому высвобождению GTP, повторному связыванию GDP, последующей мономеризации LRRK2 и возвращению в цитозоль [26] (Creative Commons Attribution License 4.0, с изменениями).

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4. Рис. 3. Влияние ингибирования киназной активности LRRK2 на пациент-специфичные клетки, ИПСК-дифференцированные нейроны, первичную культуру макрофагов на восстановление функций GCaзы. Показано влияние ингибирования киназной активности LRRK2 на увеличение активности кислой сфингомиелиназы (ASMaзы) и альфа-галактозидазы (GLA) в ИПСК-дифференцированных нейронах пациентов с GBA1-БП и галактозилцерамидазы (GALC) в ИПСК-дифференцированных нейронах пациентов с LRRK2-БП.

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