Targeting Rab6/Km23-1 Mediated Compartmentalized Trafficking as a Novel Therapeutic Approach to Alzheimer's Disease
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Abstract
Alzheimer’s Disease (AD) is a prevalent neurodegenerative disease in not only the US but worldwide. Approximately, as of 2020, around 5.8 million Americans, ages 65 and over may be living with AD. AD is a disease where the patient slowly has their mental process deteriorate, causing the patient to not be able to perform everyday tasks, causing an amnesia-like memory retention, and eventually, in severe cases, ending in an vegetative state, and requiring 24/7 care. AD can either be passed down generation to generation or cases can be sporadic, which is more common. Through the years, researchers have focused on an array of hypotheses on the disease pathogenesis and the Amyloid Hypothesis is the most studied. At the molecular level, amyloid beta (Aβ) plaques derive from the breakdown of a protein names amyloid precursor protein (APP). Amyloid fragments clump together and form plaques that accumulate between neurons and destroy cell functions. Many therapies have been targeted to the downstream effects of amyloid beta formation. Unfortunately, these therapies had little success in reducing the cell brain destruction caused by AD so a novel and fresh approach to AD therapy is greatly needed. In this study, we focus on two proteins, Rab6 and Km23-1 that may play an important role in the formation of amyloid plaques by mediating trafficking of APP in the neuronal cell. Our hypothesis is that the interaction between Km23-1 and Rab6 contributes to the cleavage of APP through over reactive Golgi trafficking, which leads to Aβ plaque formation. If this hypothesis is confirmed, targeting the Rab6/Km23-1 protein complex becomes a potentially attractive pharmacological strategy for AD. The work presented in this thesis contributes two major achievements: for the first time, we demonstrated that Rab6 and Km23-1 form a protein complex in vitro, and 2) we developed an experimental pipeline to use the mass spectrometry based protein painting technology to identify functionally relevant hot spots of interaction. Information derived from protein painting can be used to design specific and potent inhibitors to disrupt the Rab6/Km23-1 protein complex.
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This thesis has been embargoed for 10 years. It will not be available until August 2030 at the earliest.
Keywords
Alzheimer’s Disease, Pull-Down Assay, Protein Painting, Gel Electrophoresis, Rab6, Km23-1 (DYNLRB1)