Dysregulation of Heat Shock Proteins in Neurodegenerative Diseases: Restorative Roles of Small Molecules and Natural Compounds

Maiti, Panchanan; Manna, Jayeeta

doi:10.1007/978-3-030-24285-5_7

Cited by 1 publication

(1 citation statement)

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“…The HSR is highly conserved across eukaryotes and characterized by the fierce production of heat shock proteins (HSPs) which mostly function in maintaining protein homeostasis 5,6 . Dysregulation of the HSR results in altered chaperone capacity and is linked to neurodegenerative diseases 7,8 and aging 9 where decreased HSR activity aggravates proteotoxicity. Cancers also hi-jack and increase HSR activity to cope with their proteotoxic burden 10 .…”

Section: Introductionmentioning

confidence: 99%

Gene dosage screens in yeast reveal core signalling pathways controlling heat adaptation

Jann

Johansson²,

Smith

et al. 2020

Preprint

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Heat stress causes proteins to unfold and lose their function, jeopardizing essential cellular processes. To protect against heat and proteotoxic stress, cells mount a dedicated stress-protective programme, the so-called heat shock response (HSR). Our understanding of the mechanisms that regulate the HSR and their contributions to heat resistance and growth is incomplete. Here we employ CRISPRi/a to down- or upregulate protein kinases and transcription factors in S. cerevisiae. We measure gene functions by quantifying perturbation effects on HSR activity, thermotolerance, and cellular fitness at 23, 30 and 38°C. The integration of these phenotypes allowed us to identify core signalling pathways of heat adaptation and reveal novel functions for the high osmolarity glycerol, unfolded protein response and protein kinase A pathways in adjusting both thermotolerance and chaperone expression. We further provide evidence for unknown cross-talk of the HSR with the cell cycle-dependent kinase Cdc28, the primary regulator of cell cycle progression. Finally, we show that CRISPRi efficiency is temperature-dependent and that different phenotypes vary in their sensitivity to knock-down. In summary, our study quantifies regulatory gene functions in different aspects of heat adaptation and advances our understanding of how eukaryotic cells counteract proteotoxic and other heat-caused damage.

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