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Characterising the stress response in human neurons derived from induced pluripotent stem cells


Bristol Medical School

About the Project

Rationale
A heat shock response (HSR) or stress response (SR) is generated in all cells following expose to elevated temperatures and various other stressors. This HSR is characterized by the suppression of normal cellular transcription and translation and the synthesis of heat shock proteins (HSPs) that protect cells from damage [1, 2]. The inducible expression of heat shock protein genes in mammals is under the control of HSF1, which is activated by multistep process following exposure to stress. As well as driving HSP gene expression following a stress, HSF1 also mediates the transcription of satellite III (Sat III) long non-coding and this leads to the formation of nuclear stress bodies (nSBs) [3]. We have found that SAFB1/2 [4, 5] an RNA binding protein that is highly expressed in neurons plays a pivotal role in Sat III formation and is a marker of nSB formation. Importantly, many different types of stress have been found to initiate a stress response but surprisingly this response has not been studied in human neurones. In addition, it is known that some rodent neuronal populations are unable to mediate the expression of heat shock proteins (hsp70) following a stress. However, it is not known if different human neuronal populations also display a differential response to stress. We also hypothesise that the conditions that cause neurodegenerative disease may also lead to an unwanted stress response (together with the formation of nSBs) in neurons and that this could lead to, unwanted and harmful alterations in the transcription of neuronal genes.

Aim
The aim of this project is to characterise the stress response in human neurones derived from induced pluripotent stem cells.

Methods
Specifically, we will compare the effect of harmful stimuli (heat, excitotoxicity, free radicals) on the formation of nSBs and the expression of heat shock proteins in human neurons. In addition, we will investigate whether, the overexpression of genes harbouring mutations associated with Parkinson’s and polyglutamine expansion diseases inhibits or promotes the production of heat shock protein expression and nuclear stress body formation.

References

1. Howarth JL, Kelly S, Keasey MP, Glover CP, Lee YB, Mitrophanous K, Chapple JP, Gallo JM, Cheetham ME, Uney JB: Hsp40 molecules that target to the ubiquitin-proteasome system decrease inclusion formation in models of polyglutamine disease. Molecular therapy : the journal of the American Society of Gene Therapy 2007, 15:1100-1105.

2. Bienemann AS, Lee YB, Howarth J, Uney JB: Hsp70 suppresses apoptosis in sympathetic neurones by preventing the activation of c-Jun. Journal of neurochemistry 2008, 104:271-278.

3. Jolly C, Konecny L, Grady DL, Kutskova YA, Cotto JJ, Morimoto RI, Vourc'h C: In vivo binding of active heat shock transcription factor 1 to human chromosome 9 heterochromatin during stress. The Journal of cell biology 2002, 156:775-781.

4. Norman M, Rivers C, Lee YB, Idris J, Uney JB: The increasing diversity of functions attributed to the SAFB family of RNA/DNA binding proteins. The Biochemical journal 2016, 473:4271-4288.

5. Rivers C, Idris J, Scott H, Rogers M, Lee YB, Gaunt J, Phylactou L, Curk T, Campbell C, Ule J, et al: iCLIP identifies novel roles for SAFB1 in regulating RNA processing and neuronal function. BMC Biol 2015, 13:111.

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