title: Lack of exacerbation of neurodegeneration in a double transgenic mouse model of mutant LRRK2 and tau.
abstract: LRRK2 (leucine-rich repeat kinase) mutations constitute the most common cause of familial Parkinson's disease (PD). Microtubule-associated protein tau mutations cause a group of neurodegenerative diseases termed tauopathies. Genome-wide association studies show that, after α-synuclein, polymorphisms in the tau gene have the second strongest genetic association with PD. In a proportion of PD patients with LRRK2 mutations, and in several transgenic animal models of LRRK2, tau hyperphosphorylation and aggregation, rather than α-synuclein aggregation, are the most prominent neuropathologic findings. To further examine the relationship between LRRK2 and tau, we crossed LRRK2 R1441G BAC transgenic mice (Mus musculus) with tau P301S mutant transgenic mice and characterized their behavioral, neuropathological and biochemical phenotypes. We found that the combination of the two mutations does not increase tau hyperphosphorylation or aggregation nor does it exacerbate the behavioral and pathological deficits previously described in the tau P301S mice. The double-mutant mice had no shortening of lifespan and no worsening of motor or memory deficits. There was no increase in the aggregation of tau or α-synuclein. Dopaminergic neuron cell counts and striatal levels of dopamine and its metabolites were unaltered. There was no exacerbation of cell loss, microgliosis or astrogliosis in multiple brain regions. These results suggest that LRRK2 and tau do not interact to exacerbate behavioral, biochemical or pathological abnormalities in neurodegeneration and that LRRK2 and tau exert their pathogenic effects through independent mechanisms.
authors: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA fadi.mikhail@uchospitals.edu.
authors: Fadi
authors: F
authors: Mikhail
authors: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Noel
authors: N
authors: Calingasan
authors: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Luca
authors: L
authors: Parolari
authors: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Aarthi
authors: A
authors: Subramanian
authors: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Lichuan
authors: L
authors: Yang
authors: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA.
authors: M
authors: M
authors: Flint Beal
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D015415:Biomarkers; D002452:Cell Count; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D010641:Phenotype; D010766:Phosphorylation; D066263:Protein Aggregation, Pathological / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016875:tau Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases