7 research outputs found
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Homeostasis of metastable proteins in Alzheimer's disease
Alzheimer’s disease (AD) is the most common cause of dementia, affecting almost 40 million people worldwide, and it is predicted that this number will rise to nearly 150 million by 2050. It results not only in enormous distress for affected individuals and carers but also a substantial economic burden on society. Although more than 100 years have passed since its discovery, no cure for AD exists, despite enormous efforts in basic and clinical research over the past few decades, due to limited understanding of its underlying mechanisms.
Neurodegenerative disorders, of which AD is an example, are highly complex disorders characterized by extensive neuronal dysfunction associated with the misfolding and aggregation of a specific set of proteins, including amyloid plaques and neurofibrillary tangles in AD. One promising avenue for progress in the field is to improve our understanding of the mechanisms by which cellular dysfunction arises from the initial protein aggregation events.
The studies described in the thesis are based on the recent finding that a large number of proteins are inherently supersaturated, being expressed at concentrations higher than their solubilities, and constituting a metastable subproteome potentially susceptible to aggregation. These studies illustrate the dependence of aggregation prone metastable proteins on the cellular degradation machineries. They also study the role of metastable proteins and their homeostasis complement in the vulnerability of various body and brain tissues to protein aggregation diseases. Using extensive sequencing data and network based systems biology approaches, they elucidate how fundamental physicochemical properties of an individual or group of proteins relate to their biological function or dysfunction.Dr. Manmohan Singh Scholarshi
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A Cell- and Tissue-Specific Weakness of the Protein Homeostasis System Underlies Brain Vulnerability to Protein Aggregation.
The phenomenon of protein misfolding and aggregation is associated with a wide range of neurodegenerative conditions that cause progressive loss of function in specific regions of the human brain. To understand the causes of the selective cell and tissue vulnerability to the formation of these deposits, we analyzed the ability of different cell and tissue types to respond, in the absence of disease, to the presence of high levels of aggregation-prone proteins. By performing a transcriptional analysis, we found that the protein homeostasis system that regulates protein aggregation is weaker in neurons than in other cell types and in brain tissues than in other body tissues. These results suggest that the intrinsic level of regulation of protein aggregation in the healthy state is correlated with the selective vulnerability of cells and tissues to protein misfolding diseases
Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins.
Mitochondria are organelles with their own genomes, but they rely on the import of nuclear-encoded proteins that are translated by cytosolic ribosomes. Therefore, it is important to understand whether failures in the mitochondrial uptake of these nuclear-encoded proteins can cause proteotoxic stress and identify response mechanisms that may counteract it. Here, we report that upon impairments in mitochondrial protein import, high-risk precursor and immature forms of mitochondrial proteins form aberrant deposits in the cytosol. These deposits then cause further cytosolic accumulation and consequently aggregation of other mitochondrial proteins and disease-related proteins, including α-synuclein and amyloid β. This aggregation triggers a cytosolic protein homeostasis imbalance that is accompanied by specific molecular chaperone responses at both the transcriptomic and protein levels. Altogether, our results provide evidence that mitochondrial dysfunction, specifically protein import defects, contributes to impairments in protein homeostasis, thus revealing a possible molecular mechanism by which mitochondria are involved in neurodegenerative diseases
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A Cell- and Tissue-Specific Weakness of the Protein Homeostasis System Underlies Brain Vulnerability to Protein Aggregation.
The phenomenon of protein misfolding and aggregation is associated with a wide range of neurodegenerative conditions that cause progressive loss of function in specific regions of the human brain. To understand the causes of the selective cell and tissue vulnerability to the formation of these deposits, we analyzed the ability of different cell and tissue types to respond, in the absence of disease, to the presence of high levels of aggregation-prone proteins. By performing a transcriptional analysis, we found that the protein homeostasis system that regulates protein aggregation is weaker in neurons than in other cell types and in brain tissues than in other body tissues. These results suggest that the intrinsic level of regulation of protein aggregation in the healthy state is correlated with the selective vulnerability of cells and tissues to protein misfolding diseases