A rat model of progressive nigral neurodegeneration induced by the Parkinson's disease-associated G2019S mutation in LRRK2.
The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is the most common genetic cause of Parkinson's disease (PD), accounting for a significant proportion of both autosomal dominant familial and sporadic PD cases. Our aim in the present study is to generate a mammalian model of mutant G2019S LRRK2 pathogenesis, which reproduces the robust nigral neurodegeneration characteristic of PD. We developed adenoviral vectors to drive neuron-specific expression of full-length wild-type or mutant G2019S human LRRK2 in the nigrostriatal system of adult rats. Wild-type LRRK2 did not induce any significant neuronal loss. In contrast, under the same conditions and levels of expression, G2019S mutant LRRK2 causes a progressive degeneration of nigral dopaminergic neurons. Our data provide a novel rat model of PD, based on a prevalent genetic cause, that reproduces a cardinal feature of the disease within a rapid time frame suitable for testing of neuroprotective strategies.
Neurodegenerative Studies Laboratory, Brain Mind Institute, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
Julien
J
Dusonchet
Olexiy
O
Kochubey
Klodjan
K
Stafa
Samuel M
SM
Young
Romain
R
Zufferey
Darren J
DJ
Moore
Bernard L
BL
Schneider
Patrick
P
Aebischer
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002452:Cell Count; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
C547428:LRRK2 protein, rat; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D004298:Dopamine
Methods Mol Med. 2002;69:389-414
11987791
Ann Neurol. 2006 Nov;60(5):557-69
17120249
Nat Neurosci. 2009 Jul;12(7):826-8
19503083
PLoS One. 2010 Sep 17;5(9):
20862245
Nat Med. 2010 Sep;16(9):998-1000
20729864
Ann Neurol. 2006 Feb;59(2):315-22
16437584
Gene Ther. 2003 Feb;10(4):337-47
12595892
Lancet. 2005 Jan 29-Feb 4;365(9457):412-5
15680456
Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14622-7
19667187
Lancet Neurol. 2008 Jul;7(7):583-90
18539534
Neuron. 2009 Aug 27;63(4):482-96
19709630
Virology. 2000 Sep 30;275(2):348-57
10998335
Lancet. 2005 Jan 29-Feb 4;365(9457):415-6
15680457
J Neurosci. 2010 Feb 3;30(5):1788-97
20130188
N Engl J Med. 2006 Jan 26;354(4):422-3
16436781
Mol Cell Neurosci. 2001 Jan;17(1):78-96
11161471
Neurobiol Dis. 2010 Dec;40(3):503-17
20659558
Neuron. 2009 Dec 24;64(6):807-27
20064389
Ann Neurol. 2006 Feb;59(2):388-93
16437559
N Engl J Med. 2006 Jan 26;354(4):424-5
16436782
Brain. 2005 Dec;128(Pt 12):3000-11
16251215