Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice

Proceedings of the National Academy of Sciences of the United States of America

Volumn 107, Issue 21, 2010, Pages 9879-9884

  Tong, Youren ^a   Yamaguchi, Hiroo ^a   Giaime, Emilie ^a   Boyle, Scott ^b   Kopan, Raphael ^b   Kelleher III, Raymond J ^a   Shen, Jie ^a  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Aging; Autophagy; Knockout; Parkinson's disease; Ubiquitin proteasome system

Indexed keywords

ALPHA SYNUCLEIN; LEUCINE RICH REPEAT KINASE 2;

AGED; ANIMAL CELL; APOPTOSIS; ARTICLE; AUTOPHAGY; CELL DEATH; CONTROLLED STUDY; DOPAMINERGIC NERVE CELL; GERM LINE; INFLAMMATION; KIDNEY MALFORMATION; MOUSE; NERVE DEGENERATION; NEUROPATHOLOGY; NONHUMAN; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN DEGRADATION; PROTEIN FUNCTION; UBIQUITINATION;

AGING; ALPHA-SYNUCLEIN; ANIMALS; APOPTOSIS; AUTOPHAGY; DOPAMINE; HOMEOSTASIS; KIDNEY DISEASES; LYSOSOMES; MICE; MICE, KNOCKOUT; OXIDATION-REDUCTION; PROTEIN-SERINE-THREONINE KINASES; UBIQUITINATION;

MUS;

EID: 77953090478     PISSN: 00278424     EISSN: 10916490     Source Type: Journal    
DOI: 10.1073/pnas.1004676107     Document Type: Article

References (38)

1. Spillantini MG, et al. (1997) Alpha-synuclein in Lewy bodies. Nature 388:839-840.
2. Paisán-Ruíz C, et al. (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44:595-600. (Pubitemid 39531224)
3. Zimprich A, et al. (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:601-607. (Pubitemid 39531225)
4. Marín I (2006) The Parkinson disease gene LRRK2: Evolutionary and structural insights. Mol Biol Evol 23:2423-2433.
5. Deng J, et al. (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 105:1499-1504. (Pubitemid 351346543)
6. Greggio E, et al. (2008) The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation. J Biol Chem 283:16906-16914.
7. Sen S, Webber PJ, West AB (2009) Dependence of leucine-rich repeat kinase 2 (LRRK2) kinase activity on dimerization. J Biol Chem 284:36346-36356.
8. Dachsel JC, et al. (2010) Heterodimerization of Lrrk1-Lrrk2: Implications for LRRK2-associated Parkinson disease. Mech Ageing Dev 131:210-214.
9. Smith WW, et al. (2006) Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat Neurosci 9:1231-1233.
10. West AB, et al. (2005) Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci USA 102:16842-16847. (Pubitemid 41688864)
11. Rubinsztein DC (2006) The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443:780-786.
12. Singleton AB (2005) Altered alpha-synuclein homeostasis causing Parkinson's disease: The potential roles of dardarin. Trends Neurosci 28:416-421.
13. Giasson BI, et al. (2002) Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34:521-533.
14. Lee MK, et al. (2002) Human alpha-synuclein-harboring familial Parkinson's disease-linked Ala-53→Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc Natl Acad Sci USA 99:8968-8973.
15. Chandra S, Gallardo G, Fernández-Chacón R, Schlüter OM, Südhof TC (2005) Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell 123: 383-396. (Pubitemid 41546670)
16. Hardy J, Lewis P, Revesz T, Lees A, Paisan-Ruiz C (2009) The genetics of Parkinson's syndromes: A critical review. Curr Opin Genet Dev 19:254-265.
17. Biskup S, et al. (2007) Dynamic and redundant regulation of LRRK2 and LRRK1 expression. BMC Neurosci, 8:102. Available at: http://www.biomedcentral. com/1471-2202/8/102.
18. Fujiwara H, et al. (2002) Alpha-synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160-164.
19. Keller JN, et al. (2004) Autophagy, proteasomes, lipofuscin, and oxidative stress in the aging brain. Int J Biochem Cell Biol 36:2376-2391. (Pubitemid 39119753)
20. Kabeya Y, et al. (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19:5720-5728.
21. Kirisako T, et al. (1999) Formation process of autophagosome is traced with Apg8/ Aut7p in yeast. J Cell Biol 147:435-446. (Pubitemid 29496349)
22. Mizushima N, Yoshimori T, Levine B (2010) Methods in mammalian autophagy research. Cell 140:313-326.
23. Komatsu M, et al. (2005) Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 169:425-434. (Pubitemid 40686693)
24. Komatsu M, et al. (2007) Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131:1149-1163. (Pubitemid 350235021)
25. Westerlund M, et al. (2008) Developmental regulation of leucine-rich repeat kinase 1 and 2 expression in the brain and other rodent and human organs: Implications for Parkinson's disease. Neuroscience 152:429-436.
26. Beglopoulos V, et al. (2004) Reduced beta-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice. J Biol Chem 279: 46907-46914. (Pubitemid 39518343)
27. Bonifati DM, Kishore U (2007) Role of complement in neurodegeneration and neuroinflammation. Mol Immunol 44:999-1010.
28. Anglade P, et al. (1997) Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease. Histol Histopathol 12:25-31. (Pubitemid 27106916)
29. McNaught KS, Olanow CW, Halliwell B, Isacson O, Jenner P (2001) Failure of the ubiquitin-proteasome system in Parkinson's disease. Nat Rev Neurosci 2:589-594. (Pubitemid 33679832)
30. Hara T, et al. (2006) Suppression of basal autophagy in neural cells causes neuro-degenerative disease in mice. Nature 441:885-889. (Pubitemid 43910423)
31. Komatsu M, et al. (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880-884. (Pubitemid 43910422)
32. Pua HH, Dzhagalov I, Chuck M, Mizushima N, He YW (2007) A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J Exp Med 204:25-31. (Pubitemid 46148752)
33. Korolchuk VI, Mansilla A, Menzies FM, Rubinsztein DC (2009) Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol Cell 33: 517-527.
34. West AB, et al. (2007) Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum Mol Genet 16: 223-232.
35. Li X, et al. (2010) Enhanced striatal dopamine transmission and motor performance with LRRK2 overexpression in mice is eliminated by familial Parkinson's disease mutation G2019S. J Neurosci 30:1788-1797.
36. Li Y, et al. (2009) Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease. Nat Neurosci 12:826-828.
37. Lin X, et al. (2009) Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein. Neuron 64:807-827.
38. Tong Y, et al. (2009) R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice. Proc Natl Acad Sci USA 106:14622-14627.