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Molecular Chaperones in Neurodegenerative Diseases: A Short Review

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GeNeDis 2016

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 987))

Abstract

Stress and misfolded proteins result to dysfunction in the cell, often leading to neurodegenerative diseases and aging. Misfolded proteins form toxic aggregates that threaten cell’s stability and normal functions. In order to restore its homeostasis, the cell activates the UPR system. Leading role in the restoration play the molecular chaperones which target the misfolded proteins with the purpose of either helping them to unfold and refold to their natural state or lead them degradation. This paper aims to present some of the most known molecular chaperones and their relation with diseases associated to protein misfolding and neurodegeneration, as well as the role of chaperones in proteostasis.

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Authors and Affiliations

  1. Bioinformatics and Human Electrophysiology Laboratory (BiHELab), Department of Informatics, Ionian University, 7 Tsirigoti Square, Corfu, Greece

    Catherine Bobori

  2. Department of Informatics, Ionian University, Corfu, Greece

    Georgia Theocharopoulou

  3. Department of Informatics, Bioinformatics and Human Electrophysiology Laboratory, Ionian University, Corfu, Greece

    Panayiotis Vlamos

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  1. Catherine Bobori
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  2. Georgia Theocharopoulou
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  3. Panayiotis Vlamos
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Correspondence to Georgia Theocharopoulou .

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  1. Department of Informatics, Bioinformatics and Human Electrophysiology Laboratory, Ionian University, Corfu, Greece

    Panayiotis Vlamos

Appendix

Appendix

Chaperone

Location

Role

Characteristics

Related disease

UPR

Lumen of ER

Halting protein translation

 

Creutzfeldt-Jakob disease,

  

Degrading misfolded proteins

 

Alzheimer’s disease, Parkinson’s disease, Huntington’s disease

  

Activating signaling pathways that increase the production of molecular chaperones apoptosis

 

Prion diseases

First chaperone

Nucleus

Assembly of nucleosomes form histones to DNA

  

Steric chaperone

 

Convey folding information into some other proteins

  

Calnexin/Calreticulin

Lumen of ER

Calnexin forms part of the quality control monitor that recognize and target abnormally folded proteins for rapid degradation

Lectin chaperones

Glycan processing

HD

  

Protein folding

  
  

Functions as a chaperone for the folding of MHC class I α-chain in the membrane of the ER

  
  

Calreticulin binds to misfolded proteins and prevents them from being exported from the endoplasmic reticulum to the Golgi apparatus

  
  

Calreticulin, an abundant ER chaperone was shown to participate in the quality control of the amyloid precursor protein

  

Crystallin

   

AD

Hsp47/ERp29

ER

Non classical molecular chaperones

Hsp47 Procollagen chaperone

 

PDI/PPI/ERp57

ER

Folding chaperones

  

Transfer chaperones (Sec61 membrane protein)

Mitochondria & ER of eukaryotes

Transport across membranes

  

GroEl/GroEs, Dnak/DnaJ/GrpC

 

Foldases

Dnak is an Hsp70 protein.

 
   

One of Hsp40 chaperones is DnaJ (75-residue protein), which interacts with DnaK (a Hsp70 chaperone) and assists in capturing substrate proteins

 

DnaJ/Hsp53

 

Holdases

DnaJ is one of Hsp40

 

GRP78/BiP,GRP94

ER

General chaperones

 

AD,PD

GRP170

    

Erp57/BiP

ER

Quality control

Recognize misfolded proteins and help their retention in the ER allowing only correctly folded proteins to the cytosol

 

Hsp60/Hsp100/Hsp90

 

Hsp100/Hsp90 Protein disaggregation and refolding

Heat shock proteins,ATP/ADP

HD, prion diseases

Hsp70/Hsp40

 

Are involved in blocking aggregation of misfolded proteins by binding to their hydrophobic segments

Hsp70 consists of ATP-binding N-terminal domain and peptide binding C-terminal domain

AD, PD, HD, prion diseases

   

Hsp70 works in tandem with Hsp40 co-chaperone

 
   

Proteins in a cell may experience partial unfolding due to variety of factors, such as temperature increase, pH change etc. Some proteins may also fail to reach their native states after synthesis. As result such proteins adopt aggregation-prone states. To prevent this Hsp70 binds to such proteins and act as a general “safe keeper” for misfolded proteins

 

Cdc48p (valosin containing protein (VCP/p97))

ER

Ubiquitin binding protein

Transport substances from ER to cytoplasm

 

PDIA3 (Protein disulfide isomeric A3)

ER

Interacts with lectin chaperones

  
  

Modulate folding of newly synthesized glycoproteins

  

X-box binding protein (XbP1)

Part of UPR

Correlates with the expression level of expressed proteins in order to adapt the folding capacity of the ER to the respective requirements

 

AD, Crohn’s disease

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Bobori, C., Theocharopoulou, G., Vlamos, P. (2017). Molecular Chaperones in Neurodegenerative Diseases: A Short Review. In: Vlamos, P. (eds) GeNeDis 2016. Advances in Experimental Medicine and Biology, vol 987. Springer, Cham. https://doi.org/10.1007/978-3-319-57379-3_20

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