Determining the efficacy of LRRK2 inhibitor therapeutics has been a challenge due to the lack of availability and systematic characterization of LRRK2 animal models. The existing LRRK2 animal models have not closely recapitulated PD-related CNS pathology and symptomology, resulting in limited translation of preclinical findings. MJFF is generating, characterizing, and distributing LRRK2 animal models in an effort to make them available at cost without any restrictions on use for the entire research community. MJFF is generating 15 LRRK2 transgenic/knockout rodent lines, out of which 4 lines (LRRK2 WT mouse, LRRK1 KO mouse, LRRK2 KO mouse, LRRK2 KO rat) are currently available. To date, MJFF funding has facilitated distribution of over 1500 LRRK2 transgenic rodents to both non-profit organizations and industry. To generate new animal models, founder lines are selected at Taconic based on genotyping, mRNA/protein expression, and copy number data, and transferred to Jackson Labs for re-derivation. Using this process, MJFF has recently generated a BAC human LRRK2 wild type mouse that has approximately 5 fold expression over endogenous LRRK2, with the R1441G, G2019S, D1994A and A2016T mutants to be generated soon in the hope that a robust phenotype will emerge. As part of the strategy to standardize and replicate published phenotypic data, MJFF has initiated the breeding and aging of both MJFF-generated and pre-existing LRRK2 models. For example, BAC human R1441G LRRK2 transgenic mice (Li et al., 2009) were aged to 4, 8, and 12 months and behavioral (rotarod, catalepsy, balance beam, and open field, etc.), neurochemical (striatal neurotransmitter concentrations), and histological (staining for alpha-synuclein, tyrosine hydroxylase, etc.) outcome measures were determined. MJFF preliminary results indicate that while there is no behavioral phenotype evident in 4 and 8 month BAC R1441G mice (Li et al., 2009), striatal dopamine and 5-HT levels are statistically lower than non-transgenic controls at 8 months of age. MJFF is also characterizing phenotypes associated with the toxic effects of knocking out LRRK2 in order to mitigate the risk of therapeutically targeting LRRK2. MJFF generated LRRK2 KO rats have no behavioral or neurochemical deficits up to 12 months of age. Since LRRK2 KO mice exhibit kidney pathology (Herzig et al., 2011; Tong et al., 2012), MJFF is currently investigating if there are similar morphological differences in kidneys of LRRK2 KO rats. All phenotypic data will be shared by creating a public database and to accelerate the availability of LRRK2 animal models.
Marco A. Baptista, Kuldip D. Dave, Shehan De Silva, Michael Sasner, Alexander Gorodinsky, Melissa J. Beck, Changu Quang, Kevin Gamber, Alastair Reith, Jon Lyon, Aude Roulois, Yasmin Aziz, Sonal S. Das, Jamie L. Eberling, Audrey Dufour, Maurizio F. Facheris, Brian K. Fiske, , Niketa Sheth, Todd B. Sherer, Alison Urkowitz and Mark Frasier