Ph.D Student | Meller Anatoly |
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Subject | Regulation of Translation in Proteotoxic Stress and Neurodegeneration-Related Protein Aggregation |
Department | Department of Medicine | Supervisor | Dr. Reut Shalgi |
Full Thesis text | ![]() |
Regulation of translation in stress conditions is critical for maintaining protein
homeostasis (proteostasis) and successfully reacting to changes in the cellular and
external environment. Proteotoxic stress, which leads to the accumulation of
misfolded proteins, can occur in diverse conditions; on the one hand, environmental
perturbations, such as heat stress, oxidative stress, ER stress and more, which cells
can experience throughout their lifetime in an external or physiological setting; On the
other hand, pathological misfolding can be caused by various neurodegenerative
disorders, such as Amyotrophic lateral sclerosis (ALS) and Huntington’s disease,
which lead to protein aggregation. Translational control is tightly coupled to
proteostasis regulation. In all of these conditions, translation can be regulated at
diverse layers and mechanisms, from classical pathways of translation initiation
through specific mechanisms regulating translation of subsets of mRNAs, to
regulation of ribosome-associated proteins and more. However, which of these
mechanisms plays a role in the various scenarios of proteostasis assaults, and how
translation is controlled globally and specifically, is still largely unresolved.
In this work, I describe the study of proteotoxicity-mediated control of translation,
examined at two different layers of regulation. First, I characterized stress-mediated
regulation of ribosome-associated chaperones, using a new method that I established,
fluorescent polysome profiling. Here I revealed dynamic regulation of the ribosome
associated chaperone mRAC in heat stress in human cells. In the second part, I
performed a transcriptome-wide analysis of transcription and translation regulation in
response to protein aggregation of mutant Huntingtin, the protein causing the
Huntington's Disease. Importantly, I was able to separate pure populations of cells
expressing aggregated proteins from those expressing mutant HTT that is not
aggregated. I characterized several gene expression programs, and found several that
were controlled exclusively at the level of translation. Furthermore, I observed a non-classical activation of ER stress pathways, including down-regulation of ER-targeted
proteins and additional changes suggesting dysregulation of proteostasis.
In summary, my study sheds light on the regulation of translation in stress conditions,
revealing interesting details of regulation under adaptive or pathological proteotoxic
stress conditions.