Related Experiment Video

Updated: Sep 30, 2025

Mechanical Stimulation-induced Calcium Wave Propagation in Cell Monolayers: The Example of Bovine Corneal Endothelial Cells
10:46

Mechanical Stimulation-induced Calcium Wave Propagation in Cell Monolayers: The Example of Bovine Corneal Endothelial Cells

Published on: July 16, 2013

16.4K

Activation of the unfolded protein response by Connexin47 mutations associated with Pelizaeus-Merzbacher-like disease

Rafael E Flores-Obando1, Mona M Freidin2, A Iván Hernández3

  • 1Department of Physiology and Pharmacology, The Robert F. Furchgott Center for Neural and Behavioral Science, State University of New York Downstate Health Sciences University, 450 Clarkson Ave, Brooklyn, New York, United States of America.

Molecular and Cellular Neurosciences
|March 11, 2022
PubMed

Insights

Pelizaeus-Merzbacher-like disease type 1 (PMLD1) mutations in Connexin47 (Cx47) cause cellular stress and apoptosis in oligodendrocytes. A milder mutation (SPG44) does not activate these pathways, suggesting a toxic gain-of-function mechanism for PMLD1.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Pelizaeus-Merzbacher-like disease type 1 (PMLD1) is a hypomyelinating disorder caused by GJC2 gene mutations, affecting Connexin47 (Cx47) protein function.
  • Cx47 is crucial for gap junction communication between oligodendrocytes (OLs) and astrocytes in the central nervous system (CNS).
  • Previous studies indicated PMLD1-associated Cx47 mutants cause loss-of-function due to protein misprocessing.

Purpose of the Study:

  • To investigate the cellular effects of specific PMLD1-associated Cx47 mutants in primary oligodendrocytes.
  • To compare the cellular impact of severe PMLD1 mutants with a milder SPG44-associated mutant.
  • To elucidate the molecular mechanisms underlying PMLD1 pathogenesis, focusing on cellular stress and apoptosis.

Main Methods:

  • Expression of wild-type and mutant Cx47 (p.P87S, p.Y269D, p.M283T for PMLD1; p.I33M for SPG44) in primary oligodendrocytes.
  • Assessment of Cx47 subcellular localization, specifically endoplasmic reticulum (ER) retention.
  • Analysis of the unfolded protein response (UPR) and apoptotic pathway activation.

Main Results:

  • PMLD1 mutants (p.P87S, p.Y269D, p.M283T) exhibited ER retention of Cx47 in primary OLs.
  • These severe mutants triggered activation of the UPR and apoptotic pathways.
  • The SPG44-associated mutant (p.I33M) displayed wild-type-like distribution and did not activate UPR or apoptotic pathways.

Conclusions:

  • Severe PMLD1-associated Cx47 mutants cause ER retention, cellular stress, and apoptosis in oligodendrocytes.
  • The milder SPG44 mutation does not induce these detrimental cellular responses.
  • These findings suggest a toxic gain-of-function mechanism contributing to PMLD1 pathogenesis, offering potential therapeutic targets.
Keywords:
Central nervous systemConnexin 47GJC2Gap junctionsMyelinOligodendrocytesPelizaeus-Merzbacher-like disease type 1Unfolded protein response

More Related Videos

Perturbing Endothelial Biomechanics via Connexin 43 Structural Disruption09:20

Perturbing Endothelial Biomechanics via Connexin 43 Structural Disruption

Published on: October 4, 2019

5.7K
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model03:45

Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model

Published on: August 8, 2022

3.8K

Related Concept Videos

The Unfolded Protein Response01:37

The Unfolded Protein Response

The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
5.2K
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.6K
Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
4.0K
Gap Junctions01:37

Gap Junctions

Multicellular organisms employ a variety of ways for cells to communicate with each other. Gap junctions are specialized proteins that form pores between neighboring cells in animals, connecting the cytoplasm between the two, and allowing for the exchange of molecules and ions. They are found in a wide range of invertebrate and vertebrate species, mediate numerous functions including cell differentiation and development, and are associated with numerous human diseases, including cardiac and...
54.5K
Post-translational Translocation of Proteins to the RER01:27

Post-translational Translocation of Proteins to the RER

A sizable fraction of proteins destined for ER are first synthesized in the cell cytosol and then transported across the ER membrane–a process called post-translational translocation. Similar to cotranslationally translocated proteins, these proteins also use the Sec translocon complex to enter the ER lumen.
Targeting proteins to the ER
Hsp40 and Hsp70 chaperone molecules bind the translated proteins in the cytosol to prevent their folding. The chaperone binding helps to keep the signal...
6.0K
Protein Import into the Peroxisomes01:27

Protein Import into the Peroxisomes

Cells contain membrane-bound organelles called peroxisomes that oxidize organic molecules by transferring hydrogen atoms to oxygen, producing hydrogen peroxide. Peroxisomes enzymatically convert the released hydrogen peroxide into water and oxygen.
Peroxisomal Protein Import:
Peroxisomes lack the genetic machinery required to code for their own proteins. Hence, most peroxisomal membrane, lumenal and transmembrane proteins are synthesized in the cytoplasm or ER and transported to the peroxisome...
3.7K