Chronic and acute LRRK2 silencing has no long-term behavioral effects, whereas wild-type and mutant LRRK2 overexpression induce motor and cognitive deficits and altered regulation of dopamine release.
BACKGROUND
Germline silencing of the PD-related protein LRRK2 does not alter glutamate or dopamine release in adult mice, but some exploratory abnormalities have been reported with ageing. Contrastingly, high levels of human LRRK2 cause locomotor alterations and cognitive deficits accompanied by reduced striatal dopamine levels, with the latter also observed in G2019S mutant mice. Comparative cognitive and motor behavioral testing of LRRK2 KO, overexpressor and mutant overexpressor mice has not previously been reported.


METHODS
Parallel, comparative behavioral characterization was performed assessing motor and cognitive abilities. Striatal antisense oligonucleotide injections were conducted to investigate the effects of acute LRRK2 silencing on behavior and dopamine fiber density. Striatal synaptosomes prepared from hG2019S mice assessed vesicular release of dopamine and its sensitivity to D2 autoreceptor stimulation.


RESULTS
Genetic ablation of LRRK2 has no long-term consequences on motor or cognitive function. Consistently, no effects on behavior or dopaminergic fiber density were observed following acute striatal silencing. Conversely, 12-month OE mice show persistent locomotor deficits and worsening of cognitive abilities; whereas, hG2019S mice display early hyperactivity and effective learning and memory that progress to decreased motor and cognitive deficits at older ages. The G2019S mutation does not affect vesicular dopamine release, but decreases its sensitivity to D2-mediated inhibition.


CONCLUSIONS
LRRK2 silencing is well tolerated in mouse, arguing PD does not result from LRRK2 loss of function. High levels of WT and G2019S LRRK2 produce similar but temporally distinct phenotypes, potentially modeling different stages of disease progression. The data implicate gain of LRRK2 function in the pathogenesis of PD.
Centre for Applied Neurogenetics, Canada.
Mattia
M
Volta
Centre for Applied Neurogenetics, Canada.
Stefano
S
Cataldi
Centre for Applied Neurogenetics, Canada.
Dayne
D
Beccano-Kelly
Centre for Applied Neurogenetics, Canada.
Lise
L
Munsie
Centre for Applied Neurogenetics, Canada.
Igor
I
Tatarnikov
Centre for Applied Neurogenetics, Canada.
Patrick
P
Chou
Centre for Applied Neurogenetics, Canada.
Sabrina
S
Bergeron
Centre for Applied Neurogenetics, Canada.
Emma
E
Mitchell
Centre for Applied Neurogenetics, Canada.
Roscoe
R
Lim
Centre for Applied Neurogenetics, Canada.
Jaskaran
J
Khinda
Isis Pharmaceuticals Inc, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Alejandro
A
Lloret
Isis Pharmaceuticals Inc, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
C Frank
CF
Bennett
Dept. of Medical Sciences, Section of Pharmacology, University of Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
Carmela
C
Paradiso
Dept. of Medical Sciences, Section of Pharmacology, University of Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
Michele
M
Morari
Centre for Applied Neurogenetics, Canada. Electronic address: mfarrer@can.ubc.ca.
Matthew J
MJ
Farrer
Centre for Applied Neurogenetics, Canada; Division of Neurology, University of British Columbia, 2215 Wesbrook Mall, Vancouver V6T 1Z3, BC, Canada. Electronic address: amilnerwood@gmail.com.
Austen J
AJ
Milnerwood
D000818:Animals; D015153:Blotting, Western; D022202:Chromosomes, Artificial, Bacterial; D003072:Cognition Disorders / Q000235:genetics*; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology*; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004298:Dopamine
Behavior; Cognition; Genetic models; LRRK2; Parkinson's disease; Synaptosomes