Dominant-negative effects of LRRK2 heterodimers: A possible mechanism of neurodegeneration in Parkinson's disease caused by LRRK2 I2020T mutation

Biochemical and Biophysical Research Communications

Volumn 430, Issue 2, 2013, Pages 560-566

  Ohta, Etsuro ^a   Kawakami, Fumitaka ^a   Kubo, Makoto ^a   Obata, Fumiya ^a  

^a KITASATO UNIVERSITY   (Japan)

Author keywords

Akt1 phosphorylation; Apoptosis; Dominant negative effect; Heterodimer; LRRK2; Parkinson's disease

Indexed keywords

HETERODIMER; HOMODIMER; HYDROGEN PEROXIDE; LEUCINE RICH REPEAT KINASE 2; PROTEIN KINASE B;

ANIMAL CELL; APOPTOSIS; ARTICLE; CELL SURVIVAL; CONTROLLED STUDY; ENZYME ACTIVATION; ENZYME ACTIVITY; MOUSE; MUTATION; NERVE DEGENERATION; NEUROBLASTOMA; NONHUMAN; PARKINSON DISEASE; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION;

APOPTOSIS; HEK293 CELLS; HUMANS; IMMUNOPRECIPITATION; MUTATION; PARKINSON DISEASE; PHOSPHORYLATION; PROTEIN MULTIMERIZATION; PROTEIN-SERINE-THREONINE KINASES; PROTO-ONCOGENE PROTEINS C-AKT;

EID: 84872320159     PISSN: 0006291X     EISSN: 10902104     Source Type: Journal    
DOI: 10.1016/j.bbrc.2012.11.113     Document Type: Article

References (28)

1. Funayama M., Hasegawa K., Kowa H., et al. New locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann. Neurol. 2002, 51:296-301.
2. Zimprich A., Biskup S., Leitner P., et al. Mutations in LRRK2 cause autosomal-dominant Parkinsonism with pleomorphic pathology. Neuron 2004, 44:601-607.
3. Paisan-Ruiz C., Jain S., Evans E.W., et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 2004, 44:595-600.
4. Funayama M., Hasegawa K., Ohta E., et al. An LRRK2 mutation as a cause for the Parkinsonism in the original PARK8 family. Ann. Neurol. 2005, 57:918-921.
5. Gasser T. Mendelian forms of Parkinson's disease. Biochim. Biophys. Acta 2009, 1792:587-596.
6. Meylan E., Tschopp J. The RIP kinases: crucial integrators of cellular stress. Trends Biochem. Sci. 2005, 30:151-159.
7. Sen S., Webber P.J., West A.B. Dependence of leucine-rich repeat kinase 2 (LRRK2) kinase activity on dimerization. J. Biol. Chem. 2009, 284:36346-36356.
8. Greggio E., Zambrano I., Kaganovich A., et al. The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation. J. Biol. Chem. 2008, 283:16906-16914.
9. Deng J., Lewis P.A., Greggio E., et al. 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 2008, 105:1499-1504.
10. Ito G., Okai T., Fujino G., et al. GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease. Biochemistry 2007, 46:1380-1388.
11. Smith W.W., Pei Z., Jiang H., et al. Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat. Neurosci. 2006, 9:1231-1233.
12. Lobbestael E., Baekelandt V., Taymans J.M. Phosphorylation of LRRK2: from kinase to substrate. Biochem. Soc. Trans. 2012, 40:1102-1110.
13. Imai Y., Gehrke S., Wang H.Q., et al. Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in drosophila. EMBO J. 2008, 27:2432-2443.
14. Jaleel M., Nichols R.J., Deak M., et al. LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson's disease mutants affect kinase activity. Biochem. J. 2007, 405:307-317.
15. West A.B., Moore D.J., Choi C., et al. Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum. Mol. Genet. 2007, 16:223-232.
16. Gloeckner C.J., Kinkl N., Schumacher A., et al. The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum. Mol. Genet. 2006, 15:223-232.
17. Luzon-Toro B., de la Torre E.R., Delgado A., et al. Mechanistic insight into the dominant mode of the Parkinson's disease-associated G2019S LRRK2 mutation. Hum. Mol. Genet. 2007, 16:2031-2039.
18. Anand V.S., Reichling L.J., Lipinski K., et al. Investigation of leucine-rich repeat kinase 2: enzymological properties and novel assays. FEBS J. 2009, 276:466-478.
19. Greggio E., Cookson M.R. Leucine-rich repeat kinase 2 mutations and Parkinson's disease: three questions. ASN NEURO 2009, 1:e00002.
20. Ohta E., Kawakami F., Kubo M., Obata F. LRRK2 directly phosphorylates Akt1 as a possible physiological substrate: impairment of the kinase activity by Parkinson's disease-associated mutations. FEBS Lett. 2011, 585:2165-2170.
21. Plowey E.D., Cherra S.J., Liu Y.J., Chu C.T. Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J. Neurochem. 2008, 105:1048-1056.
22. Ohta E., Katayama Y., Kawakami F., et al. I2020T leucine-rich repeat kinase 2, the causative mutant molecule of familial Parkinson's disease, has a higher intracellular degradation rate than the wild-type molecule. Biochem. Biophys. Res. Commun. 2009, 390:710-715.
23. Ohta E., Kubo M., Obata F. Prevention of intracellular degradation of I2020T mutant LRRK2 restores its protectivity against apoptosis. Biochem. Biophys. Res. Commun. 2010, 391:242-247.
24. Li T., Yang D., Sushchky S., et al. Models for LRRK2-linked Parkinsonism. Parkinsons Dis. 2011, 942412.
25. Ito G., Iwatsubo T. Re-examination of the dimerization state of leucine-rich repeat kinase 2: predominance of the monomeric form. Biochem. J. 2012, 441:987-994.
26. Berger Z., Smith K.A., Lavoie M.J. Membrane localization of LRRK2 is associated with increased formation of the highly active LRRK2 dimer and changes in its phosphorylation. Biochem. 2010, 49:5511-5523.
27. Andres-Mateos E., Mejias R., Sasaki M., et al. Unexpected lack of hypersensitivity in LRRK2 knock-out mice to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). J. Neurosci. 2009, 29:15846-15850.
28. Tong Y., Yamaguchi H., Giaime E., et al. Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of alpha-synuclein, and apoptotic cell death in aged mice. Proc. Natl. Acad. Sci. USA 2010, 107:9879-9884.