New JAX® Mice for Parkinson's Disease Research

JAX® NOTES Issue 515, Fall 2009

New Mouse Models Faithfully Recapitulate Human Parkinson's Disease

Advances in genetic engineering are rapidly increasing the number of Parkinson’s disease (PD) mouse models that faithfully recapitulate the human disease process. The JAX Parkinson's Disease Mouse Model Resource (PDMMR; JAX® NOTES 2007) provides many of these newly characterized PD models. Recently, the Michael J. Fox Foundation awarded the PDMMR funding to distribute additional new models license-free (in the near future) and enable high-impact collaborations (JAX® NOTES 2009). In the past several months, the PDMMR has imported and developed the following two new sets of JAX® Mice models for PD research:

LRRK2 Mutants

Mutations in the human leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of PD. Thanks to a collaborative research team led by Dr. Chenjian Li, Department of Neurology and Neurosciences, Weill Medical College of Cornell University (Li et al. 2009), JAX will soon be distributing two strains for studying the effects of LRRK2 mutations:

FVB/N-Tg(LRRK2*R1441G)135Cjli/J 009604

  • Expresses human LRRK2 (R1441G) BAC directed by its endogenous promoter/enhancer
  • Recapitulates the age-dependent and levodopa-responsive hypokinetic motor deficits, neurochemical, and histopathological features of PD
  • Provides a robust in vivo model to investigate disease pathogenesis and potential therapies

FVB/N-Tg(LRRK2)1Cjli/J 009610

  • Overexpresses a wild-type, full-length human LRRK2 BAC directed by its endogenous promoter/enhancer
  • Control for strain 009604 (above)
  • In contrast to mutant LRRK2 strain above, exhibits slightly more motor activity than non-transgenic wild-type controls

Note: Not-for-profit entities may obtain these strains without a license. Due to restrictions imposed by the donating institution, for-profit entities need a license from Cornell University.

Dr. Li

Dr. Chenjian Li and his laboratory staff

According to Dr. Li, the LRRK2R1441G mouse (009604) is ". . . the first reported mouse model for LRRK2 mutations, and it recapitulates some key PD-like phenotypes. An interesting feature of this mouse is its age-dependent and progressive movement deficit, which is L-dopa responsive. Additionally, the construct makes use of a bacterial artificial chromosome (BAC) that covers the whole human LRRK2 gene" (Carlson and Li 2009).

Alpha-Synuclein Mutants

Mutations in the human alpha-synuclein (SNCA) gene play important roles in the pathogenesis of familial and sporadic PD. Alpha-synuclein is a major component of Lewy bodies, a hallmark of PD pathology. Dr. Darren Moore, formerly at Johns Hopkins University School of Medicine and now at the Brain Mind Institute of the Ecole Polytechnique Fédérale de Lausanne (EPFL), in Switzerland, and Dr. Ted Dawson of the Johns Hopkins University School of Medicine, recently donated four new PD models to the PDMMR (Daher et al. 2009; Savitt et al. 2005):

B6;129-Gt(ROSA)26Sortm2(SNCA*119)Djmo/TmdJ 008889

  • Widespread expression of human α-Syn119 blocked by an upstream loxP-flanked STOP sequence
  • When crossed with strain B6.Cg-Tg(Th-cre)1Tmd/J (008601), produces offspring that express the familial PD-associated Syn119 C-terminal truncation of SNCA (human α-Syn119) gene and display a significant reduction of striatal dopamine at 10-11 months
  • May model a presymptomatic stage of PD before neuronal loss

B6;129-Gt(ROSA)26Sortm1(SNCA*A53T)Djmo/TmdJ 008883

  • Widespread expression of human A53T α-Syn blocked by an upstream loxP-flanked STOP sequence
  • When crossed to strain B6.Cg-Tg(Th-cre)1Tmd/J (008601), produces offspring that express the familial PD-associated A53T missense mutation of SNCA (human A53T α-Syn)
  • May model a presymptomatic stage of PD before neuronal loss

B6;129-Gt(ROSA)26Sortm3(SNCA*E46K)Djmo/TmdJ 008886

  • Widespread expression of human E46K α-Syn blocked by an upstream loxP-flanked STOP sequence
  • When crossed to strain B6.Cg-Tg(Th-cre)1Tmd/J (008601), produces offspring that express the E46K missense mutantion of SNCA (human E46K α-Syn); mutation associated with familial PD, dementia, and visual hallucinations

B6.Cg-Tg(Th-cre)1Tmd/J 008601

  • Rat tyrosine hydroxylase (TH) promoter directs Cre expression to catecholaminergic cells and in many projection areas of these neuronal populations
  • May be used to generate conditional mutations in these cells for studying dopaminergic cell function, PD, and other neurodegenerative disorders
  • Cre expressed in several areas not typically thought to have active TH expression, including the lateral septal nucleus, accessory olfactory bulb, suparafascicular thalamus, and pretectal area
  • Some TH-negative cells closely clustered around and within TH-positive nuclei exhibit Cre activity

Note: Not-for-profit entities may obtain these strains without a license. Due to restrictions imposed by the donating institution, for-profit entities need a license from Johns Hopkins University

Dr. Moore

Dr. Darren Moore believes the alpha-synuclein
mutants will provide a unique resource for modeling
various aspects of PD.

The first three strains each harbor a unique floxed mutant SNCA transgene. When bred to Cre-expressing strains, they produce conditional mutants that can be used to study PD-related pathophysiology, including progressive dopaminergic neurodegeneration, Lewy body formation, and synaptic plasticity. These strains may also be used to analyze other neurodegenerative disorders associated with SNCA mutations.

By mating these three strains (or offspring produced by mating any combination of them) to strains that express Cre recombinase in specific cell types, investigators can study the effects of expressing different combinations of mutant SNCA alleles in various neuronal subsets. For example, a collaborative research team led by Dr. Darren Moore (Daher et al. 2009) mated these strains to B6.Cg-Tg(Nes-cre)1Kln/J (003771), which expresses Cre pan-neuronally, and B6.Cg-Tg(Th-cre)1Tmd/J (008601 - the fourth strain described above), which expresses Cre selectively in the dopaminergic neurons that are vulnerable in PD (Savitt et al. 2005). Thus, they were able to compare SNCA expression in all neurons to that in only the dopaminergic neurons. Researchers can also treat these strains with neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to study the effects of aging and environmental factors on the role of SNCA in the pathogenesis of PD.

According to Dr. Moore, "The ROSA26-Synuclein conditional transgenic mice will provide a unique resource for modeling various aspects of nigrostriatal pathway dopaminergic dysfunction in Parkinson’s disease, and may be useful for investigating the pathophysiology of other related neurodegenerative synucleinopathies".

To register interest in these strains, follow the links to their respective strain datasheets. We will send you periodic updates on the status of these colonies and advance notice (typically three weeks) of their availability. You will then have the opportunity to order the strains before they are publicly available.

The JAX Parkinson's Disease Mouse Model Resource

The JAX Parkinson's Disease Mouse Model Resource harbors other unique PD models, including the following:

  • Transgenic strains expressing various human alpha-synuclein mutations driven by different promoters
  • Alpha-, beta- and gamma synuclein (Snca, Sncb, Sncg) knockouts
  • Beta-synuclein (Sncb) knockouts
  • Parkin (Park2) knockouts
  • DJ-1 (Park7) knockouts
  • Research tool strains, including transgenics that express marker genes in affected brain regions
  • Strains allowing regulated gene expression (e.g., Cre-recombinase and tet-inducible promoters) in specific neuronal populations

Other JAX Resources for Researching Parkinson’s

  • Neurobiology Disease Resource Manual: summarizes neurobiology research conducted by JAX scientists, describes a select group of JAX® Mice models for neurobiology research, describes JAX® Services, courses and conferences, and provides online resources that can facilitate neurobiology research (order a complimentary copy)
  • Research Tools Manual: introduces Cre-lox, FLP-FRT, Tet, fluorescent protein-expressing, and lacZ technologies, describes features and research applications of selected JAX® Mice research tool strains, and describes JAX® Services that may facilitate your research (order a complimentary copy)
  • JAX® In Vivo Services: cost-effective, customizable, unmatched experience in novel compound evaluation and phenotyping more than 100 mouse strains in many therapeutic areas, including the MPTP-induced PD model and other neuromuscular/neurodegenerative disease models

References

Carlson K and Li Y. 2009. First published Lrrk2 mutation mouse model of PD: Q&A with Dr. Chenjian Li. PD online research.

Daher JPL, Ying M, Banerjee R, McDonald RS, Hahn MD, Yang L, Beal MF, Thomas B, Dawson VL, Dawson TM, Moore DJ. 2009. Conditional transgenic mice expressing C-terminally truncated human alpha-synuclein (alphaSyn119) exhibit reduced striatal dopamine without loss of nigrostriatal pathway dopaminergic neurons. Mol Neurodegener 4:34.

JAX® NOTES. 2009. Michael J. Fox Foundation and JAX collaborate to distribute Parkinson’s disease models. JAX® NOTES 514:3.

JAX® NOTES. 2007. New Parkinson’s Disease Mouse Model Resource. JAX® NOTES 506:11

Li Y, Liu W, Oo TF, Wang L, Tang Y, Jackson-Lewis V, Zhou C, Geghman K, Bogdanov M, Przedborski S, Beal MF, Burke RE, Li C. 2009. Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease. Nat Neurosci 12:826-8.

Savitt JM, Jang SS, Mu W, Dawson VL, Dawson TM. 2005. Bcl-x is required for the proper development of the mouse substantia nigra. J Neurosci 25:6721-8.