Developing Gene Therapy Methods to Inhibit a BAG Family Co-chaperone Protein in Rat Substantia Nigra
Year: 2016
Type: dissertation
Abstract: Parkinsonâ s disease (PD) is a progressive neurodegenerative disorder affecting dopaminergic neurons in the substantia nigra (SN). Bcl2-associated athanogene 5 (BAG5) is a co-chaperone that promotes dopaminergic cell death in animal models of PD and dopaminergic degeneration. BAG5 also inhibits Hsp70 and parkin, which are protective in animal models of PD, and interacts with several other proteins implicated in PD pathogenesis. Thus, BAG5 represents a promising therapeutic target for PD. This thesis describes the development of a viral vector that can deliver shRNA against BAG5 to rat SN. We identified shRNAs that efficiently knocked down BAG5 in two cell lines and packaged them into lentivirus (LV) and adeno-associated virus (AAV) 1/2 vectors. AAV-shBAG5 demonstrated superior expression in SN compared to LV. In rat SN, AAV-shBAG5 produced significant BAG5 knockdown and protected neurons from axotomy injury. This work provides the foundation for future studies of BAG5 knockdown in rat models of PD.
Source: TSpace (University of Toronto)
Author: Stanley Li
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2936720448