8u8b

Structural highlights

Disease

LRRK2_HUMAN Defects in LRRK2 are the cause of Parkinson disease type 8 (PARK8) [MIM:607060. A slowly progressive neurodegenerative disorder characterized by bradykinesia, rigidity, resting tremor, postural instability, neuronal loss in the substantia nigra, and the presence of neurofibrillary MAPT (tau)-positive and Lewy bodies in some patients.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34]}

Function

LRRK2_HUMAN May play a role in the phosphorylation of proteins central to Parkinson disease. Phosphorylates PRDX3. May also have GTPase activity. Positively regulates autophagy through a calcium-dependent activation of the CaMKK/AMPK signaling pathway. The process involves activation of nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, increase in lysosomal pH, and calcium release from lysosomes.^{[35] [36] [37] [38]}

References

1. ↑ Angeles DC, Gan BH, Onstead L, Zhao Y, Lim KL, Dachsel J, Melrose H, Farrer M, Wszolek ZK, Dickson DW, Tan EK. Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death. Hum Mutat. 2011 Dec;32(12):1390-7. doi: 10.1002/humu.21582. Epub 2011 Sep 12. PMID:21850687 doi:10.1002/humu.21582
2. ↑ Gloeckner CJ, Kinkl N, Schumacher A, Braun RJ, O'Neill E, Meitinger T, Kolch W, Prokisch H, Ueffing M. The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum Mol Genet. 2006 Jan 15;15(2):223-32. Epub 2005 Dec 1. PMID:16321986 doi:10.1093/hmg/ddi439
3. ↑ West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16842-7. Epub 2005 Nov 3. PMID:16269541 doi:10.1073/pnas.0507360102
4. ↑ Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Muller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004 Nov 18;44(4):601-7. PMID:15541309 doi:10.1016/j.neuron.2004.11.005
5. ↑ Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J, van der Brug M, Lopez de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Marti-Masso JF, Perez-Tur J, Wood NW, Singleton AB. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron. 2004 Nov 18;44(4):595-600. PMID:15541308 doi:S0896627304006890
6. ↑ Adams JR, van Netten H, Schulzer M, Mak E, Mckenzie J, Strongosky A, Sossi V, Ruth TJ, Lee CS, Farrer M, Gasser T, Uitti RJ, Calne DB, Wszolek ZK, Stoessl AJ. PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation. Brain. 2005 Dec;128(Pt 12):2777-85. Epub 2005 Aug 4. PMID:16081470 doi:awh607
7. ↑ Toft M, Sando SB, Melquist S, Ross OA, White LR, Aasly JO, Farrer MJ. LRRK2 mutations are not common in Alzheimer's disease. Mech Ageing Dev. 2005 Nov;126(11):1201-5. PMID:16087219 doi:S0047-6374(05)00149-1
8. ↑ Kachergus J, Mata IF, Hulihan M, Taylor JP, Lincoln S, Aasly J, Gibson JM, Ross OA, Lynch T, Wiley J, Payami H, Nutt J, Maraganore DM, Czyzewski K, Styczynska M, Wszolek ZK, Farrer MJ, Toft M. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet. 2005 Apr;76(4):672-80. Epub 2005 Feb 22. PMID:15726496 doi:S0002-9297(07)62878-X
9. ↑ Hernandez DG, Paisan-Ruiz C, McInerney-Leo A, Jain S, Meyer-Lindenberg A, Evans EW, Berman KF, Johnson J, Auburger G, Schaffer AA, Lopez GJ, Nussbaum RL, Singleton AB. Clinical and positron emission tomography of Parkinson's disease caused by LRRK2. Ann Neurol. 2005 Mar;57(3):453-6. PMID:15732108 doi:10.1002/ana.20401
10. ↑ Aasly JO, Toft M, Fernandez-Mata I, Kachergus J, Hulihan M, White LR, Farrer M. Clinical features of LRRK2-associated Parkinson's disease in central Norway. Ann Neurol. 2005 May;57(5):762-5. PMID:15852371 doi:10.1002/ana.20456
11. ↑ Lesage S, Ibanez P, Lohmann E, Pollak P, Tison F, Tazir M, Leutenegger AL, Guimaraes J, Bonnet AM, Agid Y, Durr A, Brice A. G2019S LRRK2 mutation in French and North African families with Parkinson's disease. Ann Neurol. 2005 Nov;58(5):784-7. PMID:16240353 doi:10.1002/ana.20636
12. ↑ Funayama M, Hasegawa K, Ohta E, Kawashima N, Komiyama M, Kowa H, Tsuji S, Obata F. An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family. Ann Neurol. 2005 Jun;57(6):918-21. PMID:15880653 doi:10.1002/ana.20484
13. ↑ Deng H, Le W, Guo Y, Hunter CB, Xie W, Jankovic J. Genetic and clinical identification of Parkinson's disease patients with LRRK2 G2019S mutation. Ann Neurol. 2005 Jun;57(6):933-4. PMID:15929036 doi:10.1002/ana.20510
14. ↑ Berg D, Schweitzer KJ, Leitner P, Zimprich A, Lichtner P, Belcredi P, Brussel T, Schulte C, Maass S, Nagele T, Wszolek ZK, Gasser T. Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson's disease*. Brain. 2005 Dec;128(Pt 12):3000-11. PMID:16251215 doi:10.1093/brain/awh666
15. ↑ Khan NL, Jain S, Lynch JM, Pavese N, Abou-Sleiman P, Holton JL, Healy DG, Gilks WP, Sweeney MG, Ganguly M, Gibbons V, Gandhi S, Vaughan J, Eunson LH, Katzenschlager R, Gayton J, Lennox G, Revesz T, Nicholl D, Bhatia KP, Quinn N, Brooks D, Lees AJ, Davis MB, Piccini P, Singleton AB, Wood NW. Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain. 2005 Dec;128(Pt 12):2786-96. Epub 2005 Nov 4. PMID:16272164 doi:10.1093/brain/awh667
16. ↑ Di Fonzo A, Tassorelli C, De Mari M, Chien HF, Ferreira J, Rohe CF, Riboldazzi G, Antonini A, Albani G, Mauro A, Marconi R, Abbruzzese G, Lopiano L, Fincati E, Guidi M, Marini P, Stocchi F, Onofrj M, Toni V, Tinazzi M, Fabbrini G, Lamberti P, Vanacore N, Meco G, Leitner P, Uitti RJ, Wszolek ZK, Gasser T, Simons EJ, Breedveld GJ, Goldwurm S, Pezzoli G, Sampaio C, Barbosa E, Martignoni E, Oostra BA, Bonifati V. Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease. Eur J Hum Genet. 2006 Mar;14(3):322-31. PMID:16333314 doi:5201539
17. ↑ Goldwurm S, Di Fonzo A, Simons EJ, Rohe CF, Zini M, Canesi M, Tesei S, Zecchinelli A, Antonini A, Mariani C, Meucci N, Sacilotto G, Sironi F, Salani G, Ferreira J, Chien HF, Fabrizio E, Vanacore N, Dalla Libera A, Stocchi F, Diroma C, Lamberti P, Sampaio C, Meco G, Barbosa E, Bertoli-Avella AM, Breedveld GJ, Oostra BA, Pezzoli G, Bonifati V. The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson's disease and originates from a common ancestor. J Med Genet. 2005 Nov;42(11):e65. PMID:16272257 doi:42/11/e65
18. ↑ Nichols WC, Pankratz N, Hernandez D, Paisan-Ruiz C, Jain S, Halter CA, Michaels VE, Reed T, Rudolph A, Shults CW, Singleton A, Foroud T. Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease. Lancet. 2005 Jan 29-Feb 4;365(9457):410-2. PMID:15680455 doi:S0140-6736(05)17828-3
19. ↑ Di Fonzo A, Rohe CF, Ferreira J, Chien HF, Vacca L, Stocchi F, Guedes L, Fabrizio E, Manfredi M, Vanacore N, Goldwurm S, Breedveld G, Sampaio C, Meco G, Barbosa E, Oostra BA, Bonifati V. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Lancet. 2005 Jan 29-Feb 4;365(9457):412-5. PMID:15680456 doi:S0140-6736(05)17829-5
20. ↑ Gilks WP, Abou-Sleiman PM, Gandhi S, Jain S, Singleton A, Lees AJ, Shaw K, Bhatia KP, Bonifati V, Quinn NP, Lynch J, Healy DG, Holton JL, Revesz T, Wood NW. A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet. 2005 Jan 29-Feb 4;365(9457):415-6. PMID:15680457 doi:10.1016/S0140-6736(05)17830-1
21. ↑ Toft M, Mata IF, Kachergus JM, Ross OA, Farrer MJ. LRRK2 mutations and Parkinsonism. Lancet. 2005 Apr 2-8;365(9466):1229-30. PMID:15811454 doi:10.1016/S0140-6736(05)74809-1
22. ↑ Kay DM, Zabetian CP, Factor SA, Nutt JG, Samii A, Griffith A, Bird TD, Kramer P, Higgins DS, Payami H. Parkinson's disease and LRRK2: frequency of a common mutation in U.S. movement disorder clinics. Mov Disord. 2006 Apr;21(4):519-23. PMID:16250030 doi:10.1002/mds.20751
23. ↑ Mata IF, Kachergus JM, Taylor JP, Lincoln S, Aasly J, Lynch T, Hulihan MM, Cobb SA, Wu RM, Lu CS, Lahoz C, Wszolek ZK, Farrer MJ. Lrrk2 pathogenic substitutions in Parkinson's disease. Neurogenetics. 2005 Dec;6(4):171-7. Epub 2005 Sep 17. PMID:16172858 doi:10.1007/s10048-005-0005-1
24. ↑ Paisan-Ruiz C, Lang AE, Kawarai T, Sato C, Salehi-Rad S, Fisman GK, Al-Khairallah T, St George-Hyslop P, Singleton A, Rogaeva E. LRRK2 gene in Parkinson disease: mutation analysis and case control association study. Neurology. 2005 Sep 13;65(5):696-700. PMID:16157901 doi:65/5/696
25. ↑ Skipper L, Shen H, Chua E, Bonnard C, Kolatkar P, Tan LC, Jamora RD, Puvan K, Puong KY, Zhao Y, Pavanni R, Wong MC, Yuen Y, Farrer M, Liu JJ, Tan EK. Analysis of LRRK2 functional domains in nondominant Parkinson disease. Neurology. 2005 Oct 25;65(8):1319-21. PMID:16247070 doi:65/8/1319
26. ↑ Farrer M, Stone J, Mata IF, Lincoln S, Kachergus J, Hulihan M, Strain KJ, Maraganore DM. LRRK2 mutations in Parkinson disease. Neurology. 2005 Sep 13;65(5):738-40. PMID:16157908 doi:65/5/738
27. ↑ Zabetian CP, Samii A, Mosley AD, Roberts JW, Leis BC, Yearout D, Raskind WH, Griffith A. A clinic-based study of the LRRK2 gene in Parkinson disease yields new mutations. Neurology. 2005 Sep 13;65(5):741-4. PMID:16157909 doi:10.1212/01.wnl.0000172630.22804.73
28. ↑ Mata IF, Taylor JP, Kachergus J, Hulihan M, Huerta C, Lahoz C, Blazquez M, Guisasola LM, Salvador C, Ribacoba R, Martinez C, Farrer M, Alvarez V. LRRK2 R1441G in Spanish patients with Parkinson's disease. Neurosci Lett. 2005 Jul 15;382(3):309-11. Epub 2005 Apr 13. PMID:15925109 doi:10.1016/j.neulet.2005.03.033
29. ↑ Infante J, Rodriguez E, Combarros O, Mateo I, Fontalba A, Pascual J, Oterino A, Polo JM, Leno C, Berciano J. LRRK2 G2019S is a common mutation in Spanish patients with late-onset Parkinson's disease. Neurosci Lett. 2006 Mar 13;395(3):224-6. Epub 2005 Nov 18. PMID:16298482 doi:10.1016/j.neulet.2005.10.083
30. ↑ Gosal D, Ross OA, Wiley J, Irvine GB, Johnston JA, Toft M, Mata IF, Kachergus J, Hulihan M, Taylor JP, Lincoln SJ, Farrer MJ, Lynch T, Mark Gibson J. Clinical traits of LRRK2-associated Parkinson's disease in Ireland: a link between familial and idiopathic PD. Parkinsonism Relat Disord. 2005 Sep;11(6):349-52. PMID:16102999 doi:S1353-8020(05)00091-X
31. ↑ Gaig C, Ezquerra M, Marti MJ, Munoz E, Valldeoriola F, Tolosa E. LRRK2 mutations in Spanish patients with Parkinson disease: frequency, clinical features, and incomplete penetrance. Arch Neurol. 2006 Mar;63(3):377-82. PMID:16533964 doi:63/3/377
32. ↑ Tan EK, Zhao Y, Skipper L, Tan MG, Di Fonzo A, Sun L, Fook-Chong S, Tang S, Chua E, Yuen Y, Tan L, Pavanni R, Wong MC, Kolatkar P, Lu CS, Bonifati V, Liu JJ. The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: genetic and functional evidence. Hum Genet. 2007 Feb;120(6):857-63. Epub 2006 Sep 30. PMID:17019612 doi:10.1007/s00439-006-0268-0
33. ↑ Paisan-Ruiz C, Nath P, Washecka N, Gibbs JR, Singleton AB. Comprehensive analysis of LRRK2 in publicly available Parkinson's disease cases and neurologically normal controls. Hum Mutat. 2008 Apr;29(4):485-90. doi: 10.1002/humu.20668. PMID:18213618 doi:10.1002/humu.20668
34. ↑ Bardien S, Lesage S, Brice A, Carr J. Genetic characteristics of leucine-rich repeat kinase 2 (LRRK2) associated Parkinson's disease. Parkinsonism Relat Disord. 2011 Aug;17(7):501-8. doi:, 10.1016/j.parkreldis.2010.11.008. PMID:21641266 doi:10.1016/j.parkreldis.2010.11.008
35. ↑ Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y, West AB, Dawson VL, Dawson TM, Ross CA. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18676-81. Epub 2005 Dec 13. PMID:16352719 doi:10.1073/pnas.0508052102
36. ↑ Zach S, Felk S, Gillardon F. Signal transduction protein array analysis links LRRK2 to Ste20 kinases and PKC zeta that modulate neuronal plasticity. PLoS One. 2010 Oct 7;5(10):e13191. doi: 10.1371/journal.pone.0013191. PMID:20949042 doi:10.1371/journal.pone.0013191
37. ↑ Angeles DC, Gan BH, Onstead L, Zhao Y, Lim KL, Dachsel J, Melrose H, Farrer M, Wszolek ZK, Dickson DW, Tan EK. Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death. Hum Mutat. 2011 Dec;32(12):1390-7. doi: 10.1002/humu.21582. Epub 2011 Sep 12. PMID:21850687 doi:10.1002/humu.21582
38. ↑ Gomez-Suaga P, Luzon-Toro B, Churamani D, Zhang L, Bloor-Young D, Patel S, Woodman PG, Churchill GC, Hilfiker S. Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. Hum Mol Genet. 2012 Feb 1;21(3):511-25. doi: 10.1093/hmg/ddr481. Epub 2011 Oct, 19. PMID:22012985 doi:10.1093/hmg/ddr481
39. ↑ Zhu H, Hixson P, Ma W, Sun J. Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM. Cell Discov. 2024 Jan 23;10(1):10. PMID:38263358 doi:10.1038/s41421-023-00639-8