Meister, Melanie

University of Groningen

English

On protein quality control, myofibrillar myopathies, and neurodegeneration

Eiwitten zijn bouwstenen van de cel en het is noodzakelijk dat zij in specifieke -vooraf bepaalde – 3-dimensionale vormen ‘gevouwen’ worden om hun functies binnen de cel te kunnen vervullen. De cel heeft een speciaal netwerk (Protein Quality Control [PQC] netwerk) die de kwaliteit van dergelijke eiwit-vouwing controleert en verkeerd gevouwen eiwitten af kan breken. Dit proces is belangrijk, omdat verkeerd gevouwen eiwitten kunnen gaan samenklonteren in zogenaamde ‘aggregraten’. Deze aggegraten zijn kenmerkend voor ziekten zoals Alzheimer’s, Parkinson’s en Huntington’s en verschillende (hart)spierziekten. Zogenaamde ‘chaperonnes’ spelen een sleutelrol in dit PQC netwerk. In dit proefschrift hebben we bestudeerd hoe verschillende chaperones een rol spelen bij deze 'eiwitaggregatie-ziekten’, waarbij wij hebben ons voornamelijk op twee specifieke chaperones hebben gericht: DNAJB6 en BAG3.We hebben aangetoond dat DNAJB6 bijzonder geschikt is om hersencellen (neuronen) te beschermen tegen de klontering die de ziekte van Huntington veroorzaakt. Daarnaast blijkt uit onze experimenten dat DNAJB6 neuronen zelfs vanuit een ander type hersenencel (astrocyten) neuronen kan beschermen. Genetische mutaties in de chaperonnes DNAJB6 en BAG3 zelf veroorzaken eveneens aggregatie-ziekten. Ons onderzoek richtte zich voornamelijk op een BAG3-mutatie die een ernstige spierziekte bij kinderen veroorzaakt. We hebben aangetoond dat deze BAG3-mutatie met maar een miniem functioneel defect catastrofale effecten heeft op het PQC netwerk en daarmee snelle degeneratie van cellen veroorzaakt.Samenvattend tone we in dit proefschrift aan hoe essentieel een goed functionerend PQC is voor de cel en daarmee voor gezond ouder worden.Proteins are the building blocks of cells and need to be folded into pre-determined 3-dimensional shapes in order to fulfil their functions. In order to control the folding states of its proteins, the cell has developed a special network of proteins. Chaperones, of which humans have over 100 different ones, are central to this protein quality control (PQC) network and support the folding or degradation of proteins. Several age-related neurodegenerative diseases (e.g. Alzheimer’s, Parkinson’s, and Huntington’s disease) and (cardio)myopathies are hall-marked by protein aggregates that imply a failure of the PQC network. In this thesis, we studied how different chaperones handle the different proteins causing these ‘protein aggregation’ diseases. We focus on 2 specific members, DNAJB6 and BAG3, which are required for the input and output of proteins to the central PQC regulator Hsp70, respectively. We show that DNAJB6 is particularly capable of protecting neurons from huntingtin aggregation, even when up-regulated in non-neuronal cells, like astrocytes, suggesting a new mode of cell-non-autonomous neuronal protection. Mutations in DNAJB6 and BAG3 themselves actually cause aggregation diseases in human. We focus on a BAG3-mutation that is associated with a severe myofibrillar myopathy in children and show that this mutation leads to a subtle defect in the output of HSP70-handled clients and a subsequent rapid, progressive collapse in PQC.Our data show the importance of fine-tuning PQC to maintain cellular fitness and support healthy aging

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   University of GroningenOn protein quality control, myofibrillar myopathies, and neurodegenerationMeister, MelanieIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2017Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Meister, M. (2017). On protein quality control, myofibrillar myopathies, and neurodegeneration. [Groningen]:University of Groningen.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 12-11-2019509712-L-sub02-st-BroekemaProcessed on: 18-4-2017Propositions pertaining to the thesis  On Protein Quality Control, Myofibri l lar Myopathies, and Neurodegeneration  Melanie Meister-Broekema  1) The correct balance between protein folding, storage, and degradation is crucial for cell viability. – Reviewed by Amie McCellan, Stephe Tam, Daniel Kaganovich & Judith Frydman, Nat Cell Biol 2005 2) Very subtle defects associated with oligomer formation of the co-chaperone BAG3P209L leads to a dramatic disruption of normal protein homeostasis and a devastating early onset disease, indicating that the meticulous regulation of protein quality control is crucial for cell vitality. This thesis  3) Although the age-related decline in the cellular ability to induce the heat shock response might contribute to disease initiation, its rescue seems to be insufficient for long-term cellular protection in most dominantly inherited proteinopathies. Yet, the apparent existence of a ‘barcode’ of chaperones with the potential to rescue aggregation for each proteinopathy suggests that disease-specific chaperone targeting may have therapeutic potential. This thesis 4) The possible existence of extracellular protein aggregate intermediates that may progress inter-cellularly provides a hitherto unappreciated extracellular stage in pathogenesis (Brundin et al. Nat Rev Mol Cell Biol, 2010). In the light of this hypothesis, glial cells become an increasingly interesting cell type with the potential to delay the propagation of neurodegenerative diseases.  5) Astrocytes may serve as reservoir for toxic, prion-like, protein species, thereby potentially preventing their progressive neuronal spread and neurodegeneration; a function that can be enhanced by DNAJB6. This thesis 6) Antimicrobial resistance poses the greatest health threat to modern society and is continuously perpetuated by the irresponsible prescription and use of antibiotics; a frustrating and paralyzing situation that could have been alleviated if more attention would have been paid to the words of the great Sir Alexander Fleming, who predicted this scenario in 1945 already.  7) The existence of life is still one of the most fascinating and most improbable coincidences on earth; yet, it seems unlikely that life would not exist elsewhere given the sheer number of stars in our galaxy and number of galaxies in our universe.  8) Science would be a wonderful thing if it would actually be about doing research.  9) As the wise Master Yoda already said a long time ago: Decide to do something or decide to leave it be. Do not just ‘try’.  10) Education should not be about the learning of facts but rather the training of the mind. 11) “I am and always will be the optimist. The hoper of far-flung hopes and the dreamer of improbable dreams” - Dr Who St. Albans, 31 March 2017 509712-sub02-st-Broekema.indd   1 18-04-17   10:34

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 University of Groningen
On protein quality control, myofibrillar myopathies, and neurodegeneration
Meister, Melanie
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date:
2017
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Meister, M. (2017). On protein quality control, myofibrillar myopathies, and neurodegeneration [Groningen]:
University of Groningen
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the
author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately
and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the
number of authors shown on this cover page is limited to 10 maximum.
Download date: 11-02-2018
 
 
 
 
 
 
 
 
On Protein Quality Control, 
Myofibril lar Myopathies, 
and Neurodegeneration 
 
 
 
 
 
 
Melanie Meister-Broekema 
 
2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The research described in this thesis was conducted at the Department of Cell 
Biology (Division: Radiation & Stress Cell Biology), Universtiy Medical Center 
Groningen, University of Groninge, The Netherlands. 
The research was supported by grants from Prinses Beatrix Fonds. 
Printing of the thesis was financially supported by the University of Groningen 
and the Graduate School for Drug Exploration (GUIDE) at the University Medial 
Center Groningen. 
Cover Design: Anna Woldring (awoldring@gmail.com) 
Thesis printed by Ipskamp Drukkers, Enschede 
 
ISBN (print): 978-90-367-9806-8 
ISBN (electronic): 978-90-367-9805-1 
 
Copyright © 2017 by Melanie Meister-Broekema. All rights reserved. No part of 
this thesis may be reproduced, stored in a retrieval system, or transmitted In any 
form or by any means without permission by the author. 
 
 
 
 
 
 
 
On Protein Quality Control,  
Myofibril lar Myopathies, and 
Neurodegeneration 
 
 
 
 
PhD thesis 
 
 
 
to obtain the degree of PhD  
at the University of Groningen  
on the authority of the  
Rector Magnificus Prof. E. Sterken 
 and in accordance with  
the decision by the College of Deans.  
 
This thesis will be defended in public on  
 
Tuesday 9 May 2017 at 11:00 hours 
 
by 
 
Melanie Meister-Broekema 
 
Born on 28 March 1985 
in Hannover, Germany 
 
 
 
Supervisor 
Prof. H. H. Kampinga 
 
Co-promoter 
Dr. S. Carra 
 
Assessment Committee 
Prof. U. L. M. Eisel 
Prof. J. van der Velden 
Prof. U. Rueb 
 
 
 
 
Paranymphs 
V. Kakkar 
P. W. K. Nagle 
 
 
 
 
 
 
 
 
 
 
 
For my amazing husband Peter,  
the love of my life; you are my warp drive 
 
And for James and minimum,  
for making my life brighter and completed 
 
 
 
 
 
 
 
 
 
Table of Contents 
Chapter 1 Introduction:  
From Chaperones to Proteinopathies;  
Protein Folding, Protein Aggregation, and 
Protein Degradation 
1 
Chapter 2 Cellular Protein Quality Control and the 
Evolution of Aggregates in SCA3 
39 
Chapter 3 Barcoding Heat Shock Proteins to Human 
Diseases:  Looking Beyond the Heat Shock 
Response 
61 
Chapter 4 DNAJB6 delays Neurodegeneration in a 
Drosophila melanogaster model for 
Huntington's disease via non-cell autonomous 
mechanisms 
99 
Chapter 5 Disturbances in Hsp70-client processing 
caused by the myopathy-associated 
BAG3P209L mutant leads to a devastating 
collapse in protein homeostasis 
127 
Chapter 6 Discussion 159 
Appendix English Summary 183 
 Nederlandse Samenvatting 189 
 Acknowledgements 197 
 List of Publications 203 
 
 
 
 
 


https://pure.rug.nl/ws/files/41849920/Chapter_4.pdf

On protein quality control, myofibrillar myopathies, and neurodegeneration

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