Unit:
Specialty Molecular Biomedicine Mechanisms of Disease, Molecular and Cellular Therapies, and BioinnovationLibrary of the School of Health Sciences
Author:
Bogiongko Marios-Evangelos
Supervisors info:
Στεφανής Λεωνίδας, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Πολίτης Παναγιώτης, Ερευνητής Γ', ΙΙΒΕΑΑ
Ξυλούρη Μαρία, Ερευνήτρια Δ', ΙΙΒΕΑΑ
Original Title:
Vulnerability of the nigrostriatal dopaminergic system in alpha-synuclein based animal models
Translated title:
Vulnerability of the nigrostriatal dopaminergic system in alpha-synuclein based animal models
Summary:
Animal models have provided us with a valuable translational tool to understand, diagnose and treat disease for many years. As far as Parkinson’s disease (PD) goes, many animal models have been implemented in recent years, in order to elucidate and better understand the pathological mechanisms of degeneration as well as to test novel therapeutic strategies. Since its discovery as a constituent of Lewy Bodies (inclusions found in the surviving substantia nigra neurons of PD patients), α-synuclein (aSyn) has been the focus of countless studies, all aiming to better understand its role in the development of the disease. Thus, a great number of genetic animal models have been generated, most of which, however, fail to fully recapitulate the entire spectrum of pathology and symptoms that are present in PD.
In 2013, a novel study (Nuber et al.,2013) introduced a transgenic animal model (BAC aSyn rat) exhibiting all the features of an ideal model for the study of this disease: aggregation pathology, loss of dopaminergic system intergrity, and non-motor and motor behavioral deficits. However, after establishing a colony in our lab we witnessed a number of phenotypic differences in our animals (GR BAC rats) compared to what the initial study (DE BAC rats) had reported. This phenomenon drove us to investigate the reason behind these differences; from both a genetic and biochemical perspective as far as aSyn goes. Interestingly, differences in both the relative copy number of the human SNCA (aSyn gene) and the levels of the protein along the nigrostriatal axis can potentially explain the presence of these differences between the two groups.
Additionally, during the past decade mutations in the GBA1 gene which encodes for glucocerebrosidase (GCase), a lysosomal enzyme responsible for the breakdown of lipids, have been labeled as the number one risk factor in developing PD. Current literature suggest an interplay between GCase and aSyn, thus our lab generated a novel murine “double-hit” viral model through striatal injection of viral vectors containing a microRNA sequence in order to downregulate GBA while at the same time overexpressing human aSyn. The aim of this project was to evaluate the temporal downregulation of GBA and investigate its effects on the nigrostriatal levels of aSyn. Our results suggest that 8 weeks is an appropriate time point for significant downregulation of GBA. Our findings also report and confirm that the downregulation of GBA leads to subsequent accumulation of human aSyn in both the striatum and the substantia nigra.
Our results indicate the suitability of the BAC aSyn rat as a tool for understanding the pre-motor phase of PD whereas the “double-hit” viral model is better suited for elucidating the mechanisms of degeneration and evaluating therapeutic strategies.
Main subject category:
Health Sciences
Keywords:
Neurodegenerative, Disorders, Animal, Models, Parkinson's, Neurobiology
Number of references:
100
