Year: 2019
Type: article
Abstract: BACKGROUND: Parkinson's disease (PD) is a synucleinopathy that has multiple neuropathological characteristics, with nigrostriatal dopamine system degeneration being a core feature. Current models of PD pathology typically fail to recapitulate several attributes of the pathogenic process and neuropathology. We aimed to define the effects of combining a mouse model exhibiting multiple PD-like changes with intrastriatal injections of α-synuclein (α-syn) pre-formed fibril (PFFs) aggregates. We employed the heterozygous Engrailed 1 (En1+/-) mouse that features several pathophysiological hallmarks of clinical PD. OBJECTIVE: To test the hypothesis that the neuropathological changes in the En1+/- mice will promote formation of α-syn aggregates following intrastriatal injections of pathogenic human α-syn PFFs. METHODS: We unilaterally injected PFFs into the striata of 1-month-old En1+/- and control wild-type mice and euthanized animals at 3 months for post-mortem analysis. RESULTS: Using immunohistochemistry and unbiased stereology, we established that PFF-injected En1+/- mice exhibited a near-threefold increase in pS129-α-syn-positive neurons in the substantia nigra compared to PFF-injected wild-type mice. The PFF-injected En1+/- mice also displayed significant increases in pS129-α-syn-positive neurons in the amygdala and ventral tegmental area; regions of known PD pathology with projections to the striatum. Additionally, we observed amplified pS129-α-syn-positive aggregation in En1+/- mice in multiple cortical regions. CONCLUSIONS: Following intrastriatal injection of PFFs, absence of an En1 allele leads to additional aggregation of pathological α-syn, potentially due to En1-loss mediated nigrostriatal impairment. We propose that further development of this double-hit model could result in a PD mouse model that predicts which experimental therapies will be effective in PD.
Source: Journal of Parkinson s Disease
DOI: 10.3233/jpd-191590
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Michael J. Fox Foundation for Parkinson's Research, Parkinson's Disease Foundation, Van Andel Research Institute, Teva Pharmaceutical Industries, Rush University, Parkinson's Foundation, Multiple System Atrophy Coalition, H. Lundbeck A/S, National Institutes of Health, National Institute on Deafness and Other Communication Disorders, National Institute of Neurological Disorders and Stroke
Awards: G2424746989, G285656620, Combining synucleinopathy and mitochondrial deficits in a novel mouse model of Parkinsons disease, G3275269120, G5193677230, G564942388, G5850682332, Does Microglial Activation Influence Propagation of Alpha-synuclein Pathology, Linking Synucleinopathy and Dysfunction of Olfactory Pathways, G9000007151, G9000041224
OpenAlex ID: W2949856622