Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of alpha-synuclein, and apoptotic cell death in aged mice.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease. LRRK2 is a large protein containing a small GTPase domain and a kinase domain, but its physiological role is unknown. To identify the normal function of LRRK2 in vivo, we generated two independent lines of germ-line deletion mice. The dopaminergic system of LRRK2(-/-) mice appears normal, and numbers of dopaminergic neurons and levels of striatal dopamine are unchanged. However, LRRK2(-/-) kidneys, which suffer the greatest loss of LRRK compared with other organs, develop striking accumulation and aggregation of alpha-synuclein and ubiquitinated proteins at 20 months of age. The autophagy-lysosomal pathway is also impaired in the absence of LRRK2, as indicated by accumulation of lipofuscin granules as well as altered levels of LC3-II and p62. Furthermore, loss of LRRK2 dramatically increases apoptotic cell death, inflammatory responses, and oxidative damage. Collectively, our findings show that LRRK2 plays an essential and unexpected role in the regulation of protein homeostasis during aging, and suggest that LRRK2 mutations may cause Parkinson's disease and cell death via impairment of protein degradation pathways, leading to alpha-synuclein accumulation and aggregation over time.
Tong
Youren
Y
Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
Yamaguchi
Hiroo
H
Giaime
Emilie
E
Boyle
Scott
S
Kopan
Raphael
R
Kelleher
Raymond J
RJ
Shen
Jie
J
D000375:Aging; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D004298:Dopamine / Q000378:metabolism; D006706:Homeostasis; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D054875:Ubiquitination; D051844:alpha-Synuclein / Q000378:metabolism*
D051844:alpha-Synuclein; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004298:Dopamine
Nat Cell Biol. 2002 Feb;4(2):160-4
11813001
Mol Cell. 2009 Feb 27;33(4):517-27
19250912
J Exp Med. 2007 Jan 22;204(1):25-31
17190837
Cell. 2007 Dec 14;131(6):1149-63
18083104
Nature. 2006 Jun 15;441(7095):880-4
16625205
Mol Biol Evol. 2006 Dec;23(12):2423-33
16966681
Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14622-7
19667187
Neuroscience. 2008 Mar 18;152(2):429-36
18272292
J Biol Chem. 2004 Nov 5;279(45):46907-14
15345711
J Biol Chem. 2009 Dec 25;284(52):36346-36356
19826009
Int J Biochem Cell Biol. 2004 Dec;36(12):2376-91
15325579
Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8968-73
12084935
J Cell Biol. 1999 Oct 18;147(2):435-46
10525546
J Cell Biol. 2005 May 9;169(3):425-34
15866887
Cell. 2005 Nov 4;123(3):383-96
16269331
Mech Ageing Dev. 2010 Mar;131(3):210-4
20144646
J Neurosci. 2010 Feb 3;30(5):1788-97
20130188
Trends Neurosci. 2005 Aug;28(8):416-21
15955578
Nature. 2006 Oct 19;443(7113):780-6
17051204
Nat Neurosci. 2009 Jul;12(7):826-8
19503083
Nat Neurosci. 2006 Oct;9(10):1231-3
16980962
Neuron. 2004 Nov 18;44(4):595-600
15541308
J Biol Chem. 2008 Jun 13;283(24):16906-14
18397888
Nature. 1997 Aug 28;388(6645):839-40
9278044
Neuron. 2004 Nov 18;44(4):601-7
15541309
Nature. 2006 Jun 15;441(7095):885-9
16625204
Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1499-504
18230735
Neuron. 2002 May 16;34(4):521-33
12062037
Cell. 2010 Feb 5;140(3):313-26
20144757
Neuron. 2009 Dec 24;64(6):807-27
20064389
Hum Mol Genet. 2007 Jan 15;16(2):223-32
17200152
Nat Rev Neurosci. 2001 Aug;2(8):589-94
11484002
Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16842-7
16269541
Histol Histopathol. 1997 Jan;12(1):25-31
9046040
Mol Immunol. 2007 Feb;44(5):999-1010
16698083
BMC Neurosci. 2007 Nov 28;8:102
18045479
EMBO J. 2000 Nov 1;19(21):5720-8
11060023
Curr Opin Genet Dev. 2009 Jun;19(3):254-65
19419854