title: LRRK2 mouse models: dissecting the behavior, striatal neurochemistry and neurophysiology of PD pathogenesis.
abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of familial Parkinson's disease (PD), resembling the sporadic disorder. Intensive effort has been directed toward LRRK2 mouse modeling and investigation, aimed at reproducing the human disease to inform mechanistic studies of pathogenesis and design of neuroprotective therapies. The physiological function of LRRK2 is still under exploration, but a clear role in striatal neurophysiology and animal behavior has emerged. Alterations in LRRK2 impair dopamine (DA) transmission, regulation and signaling, in addition to corticostriatal synaptic plasticity. Consistently, several subtle abnormalities in motor and nonmotor abilities have been demonstrated in LRRK2 genetic mouse models, generally paralleling preclinical symptoms of early DA dysfunction. However, the variability in model design and phenotypes observed requires a critical approach in interpreting the results, adapting the model used to the specific research question. Etiologically appropriate knockin mice might represent the ultimate animal model in which to study early disease mechanisms and therapies as well as to investigate drug effectiveness and off-target consequences.
authors.affiliation: Center for Biomedicine, EURAC Research, Via Galvani 31, Bolzano 39100, Italy mattia.volta@eurac.edu melrose.heather@mayo.edu.
authors.forename: Mattia
authors.initials: M
authors.lastname: Volta
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, U.S.A. mattia.volta@eurac.edu melrose.heather@mayo.edu.
authors.forename: Heather
authors.initials: H
authors.lastname: Melrose
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics / Q000378:metabolism*; D008822:Mice, Transgenic; D009154:Mutation; D009448:Neurochemistry / Q000379:methods*; D009482:Neurophysiology / Q000379:methods*; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D014793:Visual Cortex / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology
chemical_list: D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse
keywords: Parkinson's disease; animal behavior; leucine-rich repeat kinase; neurotransmission; striatum