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LRRK2  -  leucine-rich repeat kinase 2

Homo sapiens

 
 
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Disease relevance of LRRK2

 

Psychiatry related information on LRRK2

  • We did not identify LRRK2 mutations in our series of dementia patients, indicating that known pathogenic mutations are not common in patients clinically diagnosed with AD [5].
  • LRRK2 mutations are not common in Alzheimer's disease [5].
 

High impact information on LRRK2

 

Chemical [10] compound and disease context of LRRK2

 

Biological context of LRRK2

Cellular Pathways implicated downstream of LRRK2

  • G2019S LRRK2 induces autophagy through a mechanism dependent upon extracellular signal regulated protein kinase activity [9]
 

Anatomical context of LRRK2

  • The results of the Sagamihara family, in combination with the unique pathological features characterized by pure nigral degeneration without Lewy bodies, provided us with valuable information for elucidating the protein structure-pathogenesis relationship for the gene product of LRRK2 [19].
  • In human tissue, LRRK2 mRNA was found in the corresponding brain areas caudatus and putamen at lower levels and dopamine neurons were also devoid of LRRK2 mRNA [20].
  • In contrast, LRRK2 deficiency leads to increased neurite length and branching [8].
  • Confocal colocalization analysis of primary cortical neurons shows partial yet significant overlap of LRRK2 immunoreactivity with markers specific for mitochondria and lysosomes [21].
  • Immunohistochemical analysis of rat and human brain tissue and primary rat cortical neurons, with LRRK2-specific antibodies, shows widespread neuronal-specific labeling localized exclusively to punctate structures within perikarya, dendrites, and axons [21].
 

Associations of LRRK2 with chemical compounds

  • A small proportion of the cells overexpressing LRRK2 contain protein aggregates, and this proportion is greatly increased by coexpression of parkin [22].
  • The LRRK2 gene is predicted to encode a large protein containing leucine-rich repeats and Ras/GTPase, tyrosine kinase-like, and WD40 domains [23].
  • RESULTS: We found a high and strikingly specific expression of LRRK2 mRNA in rodent striatum and parts of cortex and no signals in dopamine neurons [20].
  • A ROC domain mutation that converts LRRK2 to a guanine nucleotide-free form (T1348N) abolishes the kinase activity of LRRK2 as well as its phosphate incorporation upon metabolic labeling [24].
  • The phosphorylation of LRRK2 was inhibited by potential inhibitors for cyclic AMP-dependent protein kinase [24].
 

Other interactions of LRRK2

  • SNCA, UCH-L1, and LRRK2 mutations cause autosomal dominant PD and the remaining gene mutations autosomal recessive PD [25].
  • Multiple mutations in the gene for the leucine-rich repeat kinase (LRRK2) cause autosomal dominant late-onset parkinsonism (PARK8) [26].
  • Neurons that express PD-associated LRRK2 mutations additionally harbor prominent phospho-tau-positive inclusions with lysosomal characteristics and ultimately undergo apoptosis [8].
  • LRRK2 Expression in Normal and Pathologic Human Brain and in Human Cell Lines [27].
  • RECENT FINDINGS: Several novel genes for monogenic forms of Parkinson's disease, such as PINK-1 for an autosomal-recessive early-onset variant, and LRRK2 for a relatively common late-onset autosomal-dominant form have recently been discovered, and several novel animal models have been generated on the basis of genes that had been found earlier [28].
 

Analytical, diagnostic and therapeutic context of LRRK2

 

References

  1. LRRK2 gene in Parkinson disease: mutation analysis and case control association study. Paisán-Ruíz, C., Lang, A.E., Kawarai, T., Sato, C., Salehi-Rad, S., Fisman, G.K., Al-Khairallah, T., St George-Hyslop, P., Singleton, A., Rogaeva, E. Neurology (2005) [Pubmed]
  2. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. 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, D.W., Meitinger, T., Strom, T.M., Wszolek, Z.K., Gasser, T. Neuron (2004) [Pubmed]
  3. Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease. Di Fonzo, A., Tassorelli, C., De Mari, M., Chien, H.F., Ferreira, J., Rohé, C.F., 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, R.J., Wszolek, Z.K., Gasser, T., Simons, E.J., Breedveld, G.J., Goldwurm, S., Pezzoli, G., Sampaio, C., Barbosa, E., Martignoni, E., Oostra, B.A., Bonifati, V. Eur. J. Hum. Genet. (2006) [Pubmed]
  4. Parkinson's disease and LRRK2: Frequency of a common mutation in U.S. movement disorder clinics. Kay, D.M., Zabetian, C.P., Factor, S.A., Nutt, J.G., Samii, A., Griffith, A., Bird, T.D., Kramer, P., Higgins, D.S., Payami, H. Mov. Disord. (2006) [Pubmed]
  5. LRRK2 mutations are not common in Alzheimer's disease. Toft, M., Sando, S.B., Melquist, S., Ross, O.A., White, L.R., Aasly, J.O., Farrer, M.J. Mech. Ageing Dev. (2005) [Pubmed]
  6. LRRK2 in Parkinson's disease: protein domains and functional insights. Mata, I.F., Wedemeyer, W.J., Farrer, M.J., Taylor, J.P., Gallo, K.A. Trends Neurosci. (2006) [Pubmed]
  7. Altered alpha-synuclein homeostasis causing Parkinson's disease: the potential roles of dardarin. Singleton, A.B. Trends Neurosci. (2005) [Pubmed]
  8. The Familial Parkinsonism Gene LRRK2 Regulates Neurite Process Morphology. Macleod, D., Dowman, J., Hammond, R., Leete, T., Inoue, K., Abeliovich, A. Neuron (2006) [Pubmed]
  9. Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. Plowey, E.D., Cherra SJ, 3.r.d., Liu, Y.J., Chu, C.T. J. Neurochem. (2008) [Pubmed]
  10. Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochondria in neurons. Cherra SJ, 3.r.d., Steer, E., Gusdon, A.M., Kiselyov, K., Chu, C.T. Am. J. Pathol. (2013) [Pubmed]
  11. Lrrk2 pathogenic substitutions in Parkinson's disease. Mata, I.F., Kachergus, J.M., Taylor, J.P., Lincoln, S., Aasly, J., Lynch, T., Hulihan, M.M., Cobb, S.A., Wu, R.M., Lu, C.S., Lahoz, C., Wszolek, Z.K., Farrer, M.J. Neurogenetics (2005) [Pubmed]
  12. LRRK2 G2019S in Families with Parkinson Disease Who Originated from Europe and the Middle East: Evidence of Two Distinct Founding Events Beginning Two Millennia Ago. Zabetian, C.P., Hutter, C.M., Yearout, D., Lopez, A.N., Factor, S.A., Griffith, A., Leis, B.C., Bird, T.D., Nutt, J.G., Higgins, D.S., Roberts, J.W., Kay, D.M., Edwards, K.L., Samii, A., Payami, H. Am. J. Hum. Genet. (2006) [Pubmed]
  13. Clinicogenetic study of mutations in LRRK2 exon 41 in Parkinson's disease patients from 18 countries. Tomiyama, H., Li, Y., Funayama, M., Hasegawa, K., Yoshino, H., Kubo, S., Sato, K., Hattori, T., Lu, C.S., Inzelberg, R., Djaldetti, R., Melamed, E., Amouri, R., Gouider-Khouja, N., Hentati, F., Hatano, Y., Wang, M., Imamichi, Y., Mizoguchi, K., Miyajima, H., Obata, F., Toda, T., Farrer, M.J., Mizuno, Y., Hattori, N. Mov. Disord. (2006) [Pubmed]
  14. Striatal dopamine transporter binding in Parkinson's disease associated with the LRRK2 Gly2019Ser mutation. Isaias, I.U., Benti, R., Goldwurm, S., Zini, M., Cilia, R., Gerundini, P., Di Fonzo, A., Bonifati, V., Pezzoli, G., Antonini, A. Mov. Disord. (2006) [Pubmed]
  15. Pathophysiology, pleiotrophy and paradigm shifts: genetic lessons from Parkinson's disease. Ross, O.A., Farrer, M.J. Biochem. Soc. Trans. (2005) [Pubmed]
  16. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Kachergus, J., Mata, I.F., Hulihan, M., Taylor, J.P., Lincoln, S., Aasly, J., Gibson, J.M., Ross, O.A., Lynch, T., Wiley, J., Payami, H., Nutt, J., Maraganore, D.M., Czyzewski, K., Styczynska, M., Wszolek, Z.K., Farrer, M.J., Toft, M. Am. J. Hum. Genet. (2005) [Pubmed]
  17. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. West, A.B., Moore, D.J., Biskup, S., Bugayenko, A., Smith, W.W., Ross, C.A., Dawson, V.L., Dawson, T.M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  18. Comprehensive evaluation of common genetic variation within LRRK2 reveals evidence for association with sporadic Parkinson's disease. Skipper, L., Li, Y., Bonnard, C., Pavanni, R., Yih, Y., Chua, E., Sung, W.K., Tan, L., Wong, M.C., Tan, E.K., Liu, J. Hum. Mol. Genet. (2005) [Pubmed]
  19. An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family. Funayama, M., Hasegawa, K., Ohta, E., Kawashima, N., Komiyama, M., Kowa, H., Tsuji, S., Obata, F. Ann. Neurol. (2005) [Pubmed]
  20. LRRK2 expression linked to dopamine-innervated areas. Galter, D., Westerlund, M., Carmine, A., Lindqvist, E., Sydow, O., Olson, L. Ann. Neurol. (2006) [Pubmed]
  21. Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Biskup, S., Moore, D.J., Celsi, F., Higashi, S., West, A.B., Andrabi, S.A., Kurkinen, K., Yu, S.W., Savitt, J.M., Waldvogel, H.J., Faull, R.L., Emson, P.C., Torp, R., Ottersen, O.P., Dawson, T.M., Dawson, V.L. Ann. Neurol. (2006) [Pubmed]
  22. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Smith, W.W., Pei, Z., Jiang, H., Moore, D.J., Liang, Y., West, A.B., Dawson, V.L., Dawson, T.M., Ross, C.A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  23. Protein kinases linked to the pathogenesis of Parkinson's disease. Shen, J. Neuron (2004) [Pubmed]
  24. GTP Binding Is Essential to the Protein Kinase Activity of LRRK2, a Causative Gene Product for Familial Parkinson's Disease. Ito, G., Okai, T., Fujino, G., Takeda, K., Ichijo, H., Katada, T., Iwatsubo, T. Biochemistry (2007) [Pubmed]
  25. Progress in familial Parkinson's disease. Mizuno, Y., Hattori, N., Yoshino, H., Hatano, Y., Satoh, K., Tomiyama, H., Li, Y. J. Neural Transm. Suppl. (2006) [Pubmed]
  26. Common variants of LRRK2 are not associated with sporadic Parkinson's disease. Biskup, S., Mueller, J.C., Sharma, M., Lichtner, P., Zimprich, A., Berg, D., Wüllner, U., Illig, T., Meitinger, T., Gasser, T. Ann. Neurol. (2005) [Pubmed]
  27. LRRK2 Expression in Normal and Pathologic Human Brain and in Human Cell Lines. Miklossy, J., Arai, T., Guo, J.P., Klegeris, A., Yu, S., McGeer, E.G., McGeer, P.L. J. Neuropathol. Exp. Neurol. (2006) [Pubmed]
  28. Genetics of Parkinson's disease. Gasser, T. Curr. Opin. Neurol. (2005) [Pubmed]
  29. The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Gloeckner, C.J., Kinkl, N., Schumacher, A., Braun, R.J., O'Neill, E., Meitinger, T., Kolch, W., Prokisch, H., Ueffing, M. Hum. Mol. Genet. (2006) [Pubmed]
  30. Clinical and positron emission tomography of Parkinson's disease caused by LRRK2. Hernandez, D.G., Paisán-Ruíz, C., McInerney-Leo, A., Jain, S., Meyer-Lindenberg, A., Evans, E.W., Berman, K.F., Johnson, J., Auburger, G., Schäffer, A.A., Lopez, G.J., Nussbaum, R.L., Singleton, A.B. Ann. Neurol. (2005) [Pubmed]
  31. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Di Fonzo, A., Rohé, C.F., Ferreira, J., Chien, H.F., Vacca, L., Stocchi, F., Guedes, L., Fabrizio, E., Manfredi, M., Vanacore, N., Goldwurm, S., Breedveld, G., Sampaio, C., Meco, G., Barbosa, E., Oostra, B.A., Bonifati, V. Lancet (2005) [Pubmed]
  32. Analysis of LRRK2 functional domains in nondominant Parkinson disease. Skipper, L., Shen, H., Chua, E., Bonnard, C., Kolatkar, P., Tan, L.C., Jamora, R.D., Puvan, K., Puong, K.Y., Zhao, Y., Pavanni, R., Wong, M.C., Yuen, Y., Farrer, M., Liu, J.J., Tan, E.K. Neurology (2005) [Pubmed]
 
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