Author: Yulong Sun

Publisher:

Published: 2018

Total Pages:

ISBN-13:

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Advances in modern medicine in the past century have dramatically improved the average life expectancy in the western world. Unfortunately, the molecular mechanisms that maintain the integrity of proteins in the body appear to be unable to keep pace. This has led to a growing prevalence of late-onset diseases involving abnormal accumulation of proteins, especially in the last century. The increase in occurrence of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and transmissible spongiform encephalopathies such as prion disease, has become a great burden to the healthcare system. All of these diseases are currently incurable and fatal, but they share the common hallmark of misfolding and aggregation of proteins within the effected neurons. The discovery and characterization of such proteins have often led to the identification of potential targets for treatment and drug design. In the case of ALS, progressive death of upper and lower motor neurons leads to full-body paralysis, and patient death from respiratory failure. The cause of ALS is currently unknown, but remarkably, regardless of the type of ALS (familial or sporadic), the RNA binding protein, TDP-43, is found in 97% of cases as neuronal inclusions, suggesting a mechanistic role in disease pathogenesis. In this thesis, several techniques are used to enable detailed biophysical characterization the TDP-43 aggregation process in solution and in model membranless organelles. Equilibrium turbidity measurements of the protein under aggregating conditions and the inhibitory effects of native-state stabilizing oligonucleotides on aggregation are presented. The modulatory effects of physiological concentrations of electrolytes on TDP-43 aggregation and their implications are also discussed. A novel technique called spatially targeted optical microproteomics (STOMP) is presented as a method to interrogate the proteomic contents of small cellular features in mammalian tissue in hope of identifying common proteins in neuronal inclusions and stress granules. Although the STOMP technique still requires refinement, the biophysical studies on TDP-43 presented here begin to unravel the complex and largely unknown etiology of what is currently a devastating and incurable disease.

Download or read book Molecular Mechanisms of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia written by Yulong Sun and published by . This book was released on 2018 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Advances in modern medicine in the past century have dramatically improved the average life expectancy in the western world. Unfortunately, the molecular mechanisms that maintain the integrity of proteins in the body appear to be unable to keep pace. This has led to a growing prevalence of late-onset diseases involving abnormal accumulation of proteins, especially in the last century. The increase in occurrence of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and transmissible spongiform encephalopathies such as prion disease, has become a great burden to the healthcare system. All of these diseases are currently incurable and fatal, but they share the common hallmark of misfolding and aggregation of proteins within the effected neurons. The discovery and characterization of such proteins have often led to the identification of potential targets for treatment and drug design. In the case of ALS, progressive death of upper and lower motor neurons leads to full-body paralysis, and patient death from respiratory failure. The cause of ALS is currently unknown, but remarkably, regardless of the type of ALS (familial or sporadic), the RNA binding protein, TDP-43, is found in 97% of cases as neuronal inclusions, suggesting a mechanistic role in disease pathogenesis. In this thesis, several techniques are used to enable detailed biophysical characterization the TDP-43 aggregation process in solution and in model membranless organelles. Equilibrium turbidity measurements of the protein under aggregating conditions and the inhibitory effects of native-state stabilizing oligonucleotides on aggregation are presented. The modulatory effects of physiological concentrations of electrolytes on TDP-43 aggregation and their implications are also discussed. A novel technique called spatially targeted optical microproteomics (STOMP) is presented as a method to interrogate the proteomic contents of small cellular features in mammalian tissue in hope of identifying common proteins in neuronal inclusions and stress granules. Although the STOMP technique still requires refinement, the biophysical studies on TDP-43 presented here begin to unravel the complex and largely unknown etiology of what is currently a devastating and incurable disease.