Neonatal AAV delivery of alpha-synuclein induces pathology in the adult mouse brain.

ABSTRACT: Abnormal accumulation of alpha-synuclein (?syn) is a pathological hallmark of Lewy body related disorders such as Parkinson's disease and Dementia with Lewy body disease. During the past two decades, a myriad of animal models have been developed to mimic pathological features of synucleinopathies by over-expressing human ?syn. Although different strategies have been used, most models have little or no reliable and predictive phenotype. Novel animal models are a valuable tool for understanding neuronal pathology and to facilitate development of new therapeutics for these diseases. Here, we report the development and characterization of a novel model in which mice rapidly express wild-type ?syn via somatic brain transgenesis mediated by adeno-associated virus (AAV). At 1, 3, and 6 months of age following intracerebroventricular (ICV) injection, mice were subjected to a battery of behavioral tests followed by pathological analyses of the brains. Remarkably, significant levels of ?syn expression are detected throughout the brain as early as 1 month old, including olfactory bulb, hippocampus, thalamic regions and midbrain. Immunostaining with a phospho-?syn (pS129) specific antibody reveals abundant pS129 expression in specific regions. Also, pathologic ?syn is detected using the disease specific antibody 5G4. However, this model did not recapitulate behavioral phenotypes characteristic of rodent models of synucleinopathies. In fact no deficits in motor function or cognition were observed at 3 or 6 months of age. Taken together, these findings show that transduction of neonatal mouse with AAV-?syn can successfully lead to rapid, whole brain transduction of wild-type human ?syn, but increased levels of wildtype ?syn do not induce behavior changes at an early time point (6 months), despite pathological changes in several neurons populations as early as 1 month.

SUBMITTER: Delenclos M 

PROVIDER: S-EPMC5481919 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature