Behavioral deficits and striatal DA signaling in LRRK2 p.G2019S transgenic rats: a multimodal investigation including PET neuroimaging
| Autor: | Natalja Funk, Mattia Volta, Matthew J. Farrer, Chenoa Mah, Jaskaran Khinda, Rick Kornelsen, Kimberley Co, Sabrina Bergeron, Katrina Yu, Saskia Biskup, Patrick Chou, Thomas Ott, A. Jon Stoessl, Vesna Sossi, Katherine Dinelle, Lise N. Munsie, Olaf Riess, Austen J. Milnerwood, Matthew D. Walker, Marta Mroczek, Stefano Cataldi, Li Ping Cao, Dayne Beccano-Kelly, Dagmar Galter |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
Pathology Parkinson's disease Dopamine Rats Sprague-Dawley genetics [Parkinson Disease] Slc18a2 protein rat Ppp1r1b protein rat metabolism [Dopamine] Phosphorylation metabolism [Neostriatum] metabolism [Vesicular Monoamine Transport Proteins] Neurodegeneration Dopaminergic Brain Parkinson Disease Protein-Serine-Threonine Kinases LRRK2 diagnostic imaging [Neostriatum] Rats Transgenic medicine.drug metabolism [Dopamine and cAMP-Regulated Phosphoprotein 32] medicine.medical_specialty Dopamine and cAMP-Regulated Phosphoprotein 32 Tyrosine 3-Monooxygenase genetics [Protein Serine-Threonine Kinases] genetics [Motor Activity] Motor Activity Protein Serine-Threonine Kinases Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 genetics [Protein-Serine-Threonine Kinases] Cellular and Molecular Neuroscience Neuroimaging Internal medicine medicine Animals Humans ddc:610 LRRK2 protein human diagnostic imaging [Brain] Dopamine Plasma Membrane Transport Proteins Tyrosine hydroxylase business.industry Receptors Dopamine D2 medicine.disease nervous system diseases Rats metabolism [Tyrosine 3-Monooxygenase] Neostriatum metabolism [Receptors Dopamine D2] Disease Models Animal Monoamine neurotransmitter Endocrinology metabolism [Brain] Positron-Emission Tomography Rotarod Performance Test Vesicular Monoamine Transport Proteins metabolism [Dopamine Plasma Membrane Transport Proteins] Neurology (clinical) business |
| Zdroj: | Journal of Parkinson's Disease 4(3), 483-498 (2014). doi:10.3233/JPD-140344 |
| DOI: | 10.3233/JPD-140344 |
| Popis: | BACKGROUND A major risk-factor for developing Parkinson's disease (PD) is genetic variability in leucine-rich repeat kinase 2 (LRRK2), most notably the p.G2019S mutation. Examination of the effects of this mutation is necessary to determine the etiology of PD and to guide therapeutic development. OBJECTIVE Assess the behavioral consequences of LRRK2 p.G2019S overexpression in transgenic rats as they age and test the functional integrity of the nigro-striatal dopamine system. Conduct positron emission tomography (PET) neuroimaging to compare transgenic rats with previous data from human LRRK2 mutation carriers. METHODS Rats overexpressing human LRRK2 p.G2019S were generated by BAC transgenesis and compared to non-transgenic (NT) littermates. Motor skill tests were performed at 3, 6 and 12 months-of-age. PET, performed at 12 months, assessed the density of dopamine and vesicular monoamine transporters (DAT and VMAT2, respectively) and measured dopamine synthesis, storage and availability. Brain tissue was assayed for D2, DAT, dopamine and cAMP-regulated phosphoprotein (DARPP32) and tyrosine hydroxylase (TH) expression by Western blot, and TH by immunohistochemistry. RESULTS Transgenic rats had no abnormalities in measures of striatal dopamine function at 12 months. A behavioral phenotype was present, with LRRK2 p.G2019S rats performing significantly worse on the rotarod than non-transgenic littermates (26% reduction in average running duration at 6 months), but with normal performance in other motor tests. CONCLUSIONS Neuroimaging using dopaminergic PET did not recapitulate prior studies in human LRRK2 mutation carriers. Consistently, LRRK2 p.G2019S rats do not develop overt neurodegeneration; however, they do exhibit behavioral abnormalities. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|