Abstract
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.
Highlights
Synucleinopathies such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are neurological disorders, that while differing significantly in their symptomatic presentation, are unified by a-synuclein aggregation and neuronal degeneration [1,2]
Transgenic animal models have been important for understanding the neuronal pathology and motor dysfunction seen in PD but lack the robust cortical pathology, replicating the cognitive dysfunction seen in DLB
We found that the use of the AAV6 serotype ensured a broad spread of expression, mainly localized to the cerebral cortices while the AAV5 serotype, while displaying a broad spread, did not show a great affinity to the cerebral cortices
Summary
Synucleinopathies such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are neurological disorders, that while differing significantly in their symptomatic presentation, are unified by a-synuclein aggregation and neuronal degeneration [1,2]. Between these two distinct diagnoses lies a spectrum of disorders usually classified as PD with dementia (PDD) [3]. Other useful animal models have been created through targeted gene delivery using viral vectors into the midbrain dopaminergic neurons of mice, rats and non-human primates [12,13,14,15,16] or the combination of both transgenics and viral vectors [17]. Likewise, targeted gene delivery has been used mainly to overexpress a-synuclein in small, well defined brain regions like the substantia nigra pars compacta (SNpc), replicating primarily motor symptoms of PD
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
