Leucine-rich repeat kinase 2 and alpha-synuclein: intersecting pathways in the pathogenesis of Parkinson's disease?
Although Parkinson's disease (PD) is generally a sporadic neurological disorder, the discovery of monogenic, hereditable forms of the disease has been crucial in delineating the molecular pathways that lead to this pathology. Genes responsible for familial PD can be ascribed to two categories based both on their mode of inheritance and their suggested biological function. Mutations in parkin, PINK1 and DJ-1 cause of recessive Parkinsonism, with a variable pathology often lacking the characteristic Lewy bodies (LBs) in the surviving neurons. Intriguingly, recent findings highlight a converging role of all these genes in mitochondria function, suggesting a common molecular pathway for recessive Parkinsonism. Mutations in a second group of genes, encoding alpha-synuclein (α-syn) and LRRK2, are transmitted in a dominant fashion and generally lead to LB pathology, with α-syn being the major component of these proteinaceous aggregates. In experimental systems, overexpression of mutant proteins is toxic, as predicted for dominant mutations, but the normal function of both proteins is still elusive. The fact that α-syn is heavily phosphorylated in LBs and that LRRK2 is a protein kinase, suggests that a link, not necessarily direct, exists between the two. What are the experimental data supporting a common molecular pathway for dominant PD genes? Do α-syn and LRRK2 target common molecules? Does LRRK2 act upstream of α-syn? In this review we will try to address these of questions based on the recent findings available in the literature.
Department of Biology, University of Padova, Via U, Bassi 58/b, 35121, Padova, Italy. luigi.bubacco@unipd.it.
Elisa
E
Greggio
Marco
M
Bisaglia
Laura
L
Civiero
Luigi
L
Bubacco
J Neurosci. 2010 Dec 15;30(50):16959-69
21159966
J Neuropathol Exp Neurol. 2009 Jul;68(7):785-96
19535993
Neuron. 2004 Nov 18;44(4):601-7
15541309
Neuron. 2010 Jan 14;65(1):66-79
20152114
Science. 2004 Aug 27;305(5688):1292-5
15333840
Science. 1997 Jun 27;276(5321):2045-7
9197268
Nat Cell Biol. 2002 Feb;4(2):160-4
11813001
Ann Neurol. 2003 Jul;54(1):135
12838532
Science. 2003 Jan 10;299(5604):256-9
12446870
J Neurosci. 2010 Mar 3;30(9):3184-98
20203178
PLoS Genet. 2010 Apr 22;6(4):e1000914
20421934
Biochem Biophys Res Commun. 2009 Dec 25;390(4):1229-34
19878656
Brain Res. 2007 Jun 25;1155:208-19
17512502
PLoS One. 2009 Dec 24;4(12):e8463
20041156
J Neurosci. 2008 Mar 26;28(13):3384-91
18367605
Proc Natl Acad Sci U S A. 2010 Nov 9;107(45):19573-8
20974939
FASEB J. 2009 Sep;23(9):2820-30
19369384
Nat Med. 2002 Jun;8(6):600-6
12042811
J Neurochem. 2009 Nov;111(3):703-15
19712061
Neurobiol Dis. 2010 Dec;40(3):503-17
20659558
J Neurosci. 2006 Nov 15;26(46):11915-22
17108165
Nat Genet. 1998 Feb;18(2):106-8
9462735
Lancet. 2004 Sep 25-Oct 1;364(9440):1167-9
15451224
Arch Neurol. 2006 Sep;63(9):1250-4
16966502
Nat Neurosci. 2005 May;8(5):657-63
15834418
Ann Neurol. 2006 Nov;60(5):557-69
17120249
J Neurosci. 2002 Apr 15;22(8):3090-9
11943812
Nat Neurosci. 2009 Jul;12(7):826-8
19503083
Biochemistry. 2003 Jul 22;42(28):8530-40
12859200
J Neurosci Res. 2008 Jun;86(8):1711-20
18214993
Nat Neurosci. 2006 Oct;9(10):1231-3
16980962
Neuron. 2004 Nov 18;44(4):595-600
15541308
FASEB J. 2009 Feb;23(2):329-40
18948383
J Biol Chem. 2008 Jun 13;283(24):16906-14
18397888
Neuron. 2006 Nov 22;52(4):587-93
17114044
Nature. 1997 Aug 28;388(6645):839-40
9278044
Nat Genet. 2009 Dec;41(12):1308-12
19915575
Hum Mol Genet. 2009 Nov 1;18(21):4022-34
19640926
J Neurosci. 2004 Jul 28;24(30):6715-23
15282274
Neuropathol Appl Neurobiol. 2008 Jun;34(3):272-83
17971075
Neuron. 1995 Feb;14(2):467-75
7857654
Cell Death Dis. 2010;1:e2
21152247
Hum Mol Genet. 2007 Mar 15;16(6):678-90
17341485
Arch Neurol. 2008 Apr;65(4):514-9
18413475
Neuron. 2000 Jan;25(1):239-52
10707987
Biochemistry. 2002 Mar 26;41(12):3855-60
11900526
J Neurochem. 2008 May;105(3):1048-56
18182054
J Neurosci Res. 2007 Feb 1;85(2):351-63
17131421
J Neurosci. 2010 Jun 16;30(24):8083-95
20554859
Biochem J. 2010 Sep 15;430(3):405-13
20659021
Nat Genet. 2009 Dec;41(12):1303-7
19915576
Ann Neurol. 2006 Feb;59(2):315-22
16437584
J Neurosci. 2002 Oct 15;22(20):8797-807
12388586
J Cell Biol. 2007 Jan 1;176(1):11-7
17200414
Ann Neurol. 2004 Feb;55(2):164-73
14755719
J Biol Chem. 2010 Nov 5;285(45):34885-98
20805224
Science. 2010 Sep 24;329(5999):1663-7
20798282
Proc Natl Acad Sci U S A. 2004 Oct 12;101(41):14966-71
15465911
Nature. 2010 Jul 29;466(7306):637-41
20671708
Ann Neurol. 2006 Nov;60(5):617-8; author reply 618-9
16847950
Sci STKE. 2004 Jul 13;2004(242):re10
15266103
Nat Med. 2008 May;14(5):501-3
18391963
J Proteome Res. 2010 Apr 5;9(4):1738-45
20108944
J Neurochem. 2010 Apr;113(2):374-88
20132485
J Neurosci. 2005 Jun 22;25(25):6016-24
15976091
Hum Mol Genet. 2006 Jan 15;15(2):223-32
16321986
J Neurobiol. 2003 Apr;55(1):14-24
12605455
Acta Neurobiol Exp (Wars). 2008;68(4):509-15
19112474
Biochem Biophys Res Commun. 2009 Nov 20;389(3):449-54
19733152
Cell Signal. 2010 May;22(5):821-7
20074637
Biochem J. 2010 Sep 15;430(3):393-404
20642453
J Neurochem. 2010 Mar;112(6):1593-604
20067578
Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20051-6
19892735
Biochem Biophys Res Commun. 2009 Sep 11;387(1):149-52
19576176
Neuroscience. 2009 Oct 6;163(2):533-9
19559761
EMBO J. 2008 Sep 17;27(18):2432-43
18701920
Hum Mol Genet. 2009 Oct 15;18(20):3955-68
19625296
Ann Neurol. 2002 Mar;51(3):296-301
11891824
Nature. 1998 Apr 9;392(6676):605-8
9560156
Biochem Biophys Res Commun. 2008 Aug 1;372(3):423-8
18492487
Oncogene. 2010 Nov 4;29(44):5895-910
20697350
Neuron. 2009 Dec 24;64(6):807-27
20064389
J Neurochem. 2007 Jul;102(1):93-102
17394548
Hum Mol Genet. 2007 Jan 15;16(2):223-32
17200152
Proc Natl Acad Sci U S A. 2010 May 25;107(21):9879-84
20457918
Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16842-7
16269541
Neurodegener Dis. 2008;5(3-4):222-4
18322396
J Neurochem. 2007 Oct;103(1):238-47
17623048
Nat Med. 2008 May;14(5):504-6
18391962
Biochemistry. 2009 Nov 24;48(46):10963-75
19824698
Curr Biol. 2007 Apr 3;17(7):592-8
17346966
Ann Neurol. 2004 Sep;56(3):336-41
15349860
Neurodegener Dis. 2010;7(1-3):175-9
20197701
ASN Neuro. 2009 Apr 14;1(1):
19570025
Biochemistry. 2001 Sep 25;40(38):11604-13
11560511
J Neurochem. 2009 May;109(4):959-68
19302196
Neurodegener Dis. 2010;7(1-3):68-75
20173330
Nat Med. 1998 Nov;4(11):1318-20
9809558
Neuroscience. 2007 Jul 29;147(4):1047-58
17611037
J Neurosci. 2010 Sep 29;30(39):13138-49
20881132
J Biol Chem. 1998 Apr 17;273(16):9443-9
9545270
PLoS Genet. 2010 Apr 08;6(4):e1000902
20386743
Science. 2003 Dec 5;302(5651):1769-72
14657499
J Neuropathol Exp Neurol. 2010 Sep;69(9):959-72
20720502
Neurobiol Dis. 2006 Aug;23(2):329-41
16750377
J Neurosci. 2009 Nov 4;29(44):13971-80
19890007
J Biol Chem. 2009 Dec 25;284(52):36346-36356
19826009
Exp Cell Res. 2008 Jun 10;314(10):2055-65
18445495
Biochem Biophys Res Commun. 2007 Jun 8;357(3):668-71
17442267
Hum Mutat. 2008 Apr;29(4):485-90
18213618
J Biol Chem. 2002 Feb 22;277(8):6344-52
11744721
J Biol Chem. 2001 Jan 26;276(4):2380-6
11060312
J Biol Chem. 2008 Aug 29;283(35):23542-56
18566453
J Neurochem. 2009 Sep;110(5):1514-22
19545277
Hum Mol Genet. 2010 Oct 1;19(19):3747-58
20624856
EMBO Rep. 2010 Jul;11(7):528-33
20489724
Neuropathology. 2003 Sep;23(3):199-202
14570287
Biochemistry. 2010 Jul 6;49(26):5511-23
20515039
J Neurosci. 2009 Jan 28;29(4):1011-6
19176810
J Biol Chem. 2000 Mar 24;275(12):8812-6
10722726
J Neurochem. 2006 Nov;99(4):1188-96
16981894
J Biol Chem. 2006 Oct 6;281(40):29739-52
16847063
Biochem J. 2007 Jul 15;405(2):307-17
17447891