Novel AAV-based rat model of forebrain synucleinopathy shows extensive pathologies and progressive loss of cholinergic interneurons

• Published in: PloS one 2014-07, Vol.9 (7), p.e100869-e100869
• Main Authors: Aldrin-Kirk, Patrick, Davidsson, Marcus, Holmqvist, Staffan, Li, Jia-Yi, Björklund, Tomas
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Alzheimer's disease; Alzheimers disease; Animal models; Animals; Animals, Newborn; Apomorphine; Autophagy; Axons - drug effects; Axons - metabolism; Basic Medicine; Biology and Life Sciences; Biomarkers; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cholinergic Neurons - drug effects; Cholinergic Neurons - pathology; Cortex (frontal); Degeneration; Dementia; Dementia disorders; Dependovirus - genetics; Disease Models, Animal; Disease Progression; Dopamine; Dopamine Agonists - pharmacology; Dopamine receptors; Exploratory Behavior - drug effects; Female; Forebrain; Gene transfer; Genetic Vectors - genetics; Humans; Inclusion bodies; Interneurons; Interneurons - drug effects; Interneurons - pathology; Laboratory animals; Lewy bodies; Lewy Body Disease - genetics; Lewy Body Disease - metabolism; Lewy Body Disease - pathology; Lewy Body Disease - physiopathology; Locomotion; Medical and Health Sciences; Medicin och hälsovetenskap; Medicine and health sciences; Medicinska och farmaceutiska grundvetenskaper; Microglia; Microglia - drug effects; Microglia - pathology; Motor Activity - drug effects; Movement disorders; Neonates; Neostriatum; Neostriatum - drug effects; Neostriatum - pathology; Neurodegeneration; Neurodegenerative diseases; Neurons; Neurosciences; Neurovetenskaper; Overexpression; Parkinson's disease; Parkinsons disease; Pathology; Phenotype; Pregnancy; Prosencephalon - metabolism; Prosencephalon - pathology; Protein Transport; Rats; Rats, Sprague-Dawley; Research and Analysis Methods; Rodents; Substantia nigra; Surgery; Synapses - drug effects; Synapses - metabolism; Synuclein; Vectors (Biology)
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0100869

Synucleinopathies, characterized by intracellular aggregation of α-synuclein protein, share a number of features in pathology and disease progression. However, the vulnerable cell population differs significantly between the disorders, despite being caused by the same protein. While the vulnerability of dopamine cells in the substantia nigra to α-synuclein over-expression, and its link to Parkinson's disease, is well studied, animal models recapitulating the cortical degeneration in dementia with Lewy-bodies (DLB) are much less mature. The aim of this study was to develop a first rat model of widespread progressive synucleinopathy throughout the forebrain using adeno-associated viral (AAV) vector mediated gene delivery. Through bilateral injection of an AAV6 vector expressing human wild-type α-synuclein into the forebrain of neonatal rats, we were able to achieve widespread, robust α-synuclein expression with preferential expression in the frontal cortex. These animals displayed a progressive emergence of hyper-locomotion and dysregulated response to the dopaminergic agonist apomorphine. The animals receiving the α-synuclein vector displayed significant α-synuclein pathology including intra-cellular inclusion bodies, axonal pathology and elevated levels of phosphorylated α-synuclein, accompanied by significant loss of cortical neurons and a progressive reduction in both cortical and striatal ChAT positive interneurons. Furthermore, we found evidence of α-synuclein sequestered by IBA-1 positive microglia, which was coupled with a distinct change in morphology. In areas of most prominent pathology, the total α-synuclein levels were increased to, on average, two-fold, which is similar to the levels observed in patients with SNCA gene triplication, associated with cortical Lewy body pathology. This study provides a novel rat model of progressive cortical synucleinopathy, showing for the first time that cholinergic interneurons are vulnerable to α-synuclein over-expression. This animal model provides a powerful new tool for studies of neuronal degeneration in conditions of widespread cortical α-synuclein pathology, such as DLB, as well an attractive model for the exploration of novel biomarkers.