Disease-modifying effects of human small heat shock proteins in zebrafish models of neurodegeneration

Neurodegenerative diseases are frequently characterised by the build-up of misfolded proteins and degeneration of brain structures. Tauopathies are a collective of >20 such diseases featuring abnormally aggregating tau, a microtubule-associated protein normally acting to stabilise these protein cargo tracks. There is currently no cure. Small heat shock proteins (sHSPs) are highly conserved molecular chaperones known to act as holding partners for substrates. Studies have reported that some sHSPs can act as chaperones for disease-related proteins to prevent their aggregation and may be beneficial in such diseases. However, there is a lack of a thorough screen of the sHSPs and their disease-modulating effects in an in vivo model. The aim of this thesis research was to screen the sHSP family to determine which, and how, any of the human sHSPs could ameliorate tau toxicity in zebrafish tauopathy models. Of all eleven sHSPs, HSPB1, B4 and B5 ameliorated morphological disease phenotypes induced by pan-neuronal expression of mutant A152T tau. HSPB4 and B5 have never been demonstrated to be beneficial in a tauopathy model in vivo, and peptides created from the central domain of these similarly ameliorated the morphological phenotype. To further investigate the underlying mechanism of action, I created and characterised a transgenic zebrafish line ubiquitously expressing human HSPB5. I demonstrate that overexpression of HSPB5 in the pan-neuronal A152T tau line results in reduced levels of hyperphosphorylated and insoluble tau. Additionally, a synthetic HSPB5 peptide similarly ameliorated morphological phenotypes by treatment via embryo immersion and reduced levels of insoluble tau. These results indicate that HSPB5 and its peptide may be of therapeutic interest for use against tauopathies as it can improve various disease phenotypes in an in vivo model.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2022

Author dc:creator

• Lager Gotaas, Ingrid

Advisors dc:contributor.advisor

• Rubinsztein, David
• Fleming, Angeleen

• small heat shock proteins
• neurodegeneration
• tauopathy
• neurodegenerative disease
• hspb5
• cryab
• zebrafish
• tau
• hspb1
• hsp27
• hspb4
• molecular chaperone

Licence

• https://creativecommons.org/licenses/by/4.0/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.91793

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/344369