Characterizing rescue of an Alzheimer's disease model in Drosophila by downregulation of heparan sulfate biosynthetic enzymes and treatment by bosutinib
Open Access
- Author:
- Swanson, Lindsey
- Area of Honors:
- Biochemistry and Molecular Biology
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Scott Brian Selleck, Thesis Supervisor
Sarah Mary Assmann, Thesis Honors Advisor - Keywords:
- Alzheimer's disease
Heparan sulfate
Lipid metabolism
Autophagy
Mitochondria
Presenilin - Abstract:
- Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss, cognitive decline, and behavioral changes. The most common causes of familial, early-onset AD are related to mutations in presenilin-1 (PSEN1). The PSEN1 gene encodes for presenilin-1 protein, which is a major component of the γ-secretase complex. This is a protease complex involved in the cleavage of transmembrane proteins. About 90% of these PSEN1 mutations are reduction or loss-of-function, and they lead to detrimental changes within cells including decreased autophagy, mitochondrial dysfunction, and abnormal lipid accumulation. Previous studies have analyzed the function of heparan sulfate-modified proteoglycans (HSPGs) in cellular pathways and their effect on AD pathology. HSPGs are found at the cell surface and in the extracellular matrix and play a critical role in growth factor action. The gene NDST1 affects the sulfation level of HS, and it has been shown that downregulating NDST1 decreases the sulfation of HS and counteracts the negative autophagic, mitochondrial, and lipid effects induced by PSEN1 downregulation. Additionally, bosutinib, an FDA-approved drug for chronic myelogenous leukemia, has also been shown to have counteractive effects similar to NDST1 but through a tyrosine kinase inhibiting pathway. The purpose of these experiments was to study the relationship between presenilin and sulfation levels as well as between presenilin and bosutinib in a Drosophila model and attempt to rescue the diseased state in these animals. This was done by knocking down Psn, a homolog of PSEN1, and sulfateless (sfl), a homolog of NDST1. Knocking down Psn led to abnormalities in mitochondria and liposome morphology. Both methods of attempted rescue- introducing a simultaneous knockdown of sfl and treating diseased flies with bosutinib- suppressed these effects to different degrees.