One of the promises of genetic association studies is better animal models for research and for development of therapeutics. Such promises are often slowly fulfilled. Twelve genetic loci that can cause Parkinson disease (PD) or parkinsonism have been identified in the last decade, but a model that fully recapitulates the pathology and behavior of the human disease has yet to emerge. Now, the latest transgenic mouse comes close. In the June 7 Nature Neuroscience, researchers led by Chenjian Li at Cornell University, New York, debut a model based on the LRRK2 gene, which was identified in 2004 (see ARF related news story). The mouse exhibits many of the defining characteristics of PD, including pathology in the axons that extend from the substantia nigra (the site of dopaminergic neuron loss in PD) to the striatum, and age-dependent movement problems that respond to L-DOPA. The latter “suggests a possible overlap with mechanisms seen in human PD patients,” wrote Mark Cookson, National Institute of Health, Bethesda, Maryland, in a comment to Alzforum (see below). “These mice provide a valid model of Parkinson disease and are a resource for the investigation of pathogenesis and therapeutics,” write the authors.
First author Yanping Li and colleagues used bacterial artificial chromosomes (BACs) containing human mutated LRRK2 (R1441G mutation that causes PD) to generate transgenic mice. The mice developed normally despite robust expression of human LRRK2 in several areas of the brain, such as cortex, cerebellum, striatum, and the ventral midbrain. By 10-12 months motor impairment was apparent, however, which cleared up with treatment with L-DOPA or the dopamine agonist apomorphine. Li and colleagues used a dopamine re-uptake blocker and microdialysis to confirm that the animals released significantly less dopamine compared to wild-type animals. Histological analysis showed that axons of dopaminergic neurons looked abnormal, containing spheroids and dystrophic neurites. The researchers also found that those axons stained positive for hyperphosphorylated tau, which has also been found in patients with the LRRK2 mutation (for more on tau in PD, see ARF spectrum series story). One thing the mice do not seem to recapitulate is the neuronal loss seen in PD. For more on this model, read Q&A on PD Online Research with senior author Chenjian Li.—Tom Fagan
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- 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. Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease. Nat Neurosci. 2009 Jul;12(7):826-8. PubMed.