Related Experiment Video

Updated: Aug 26, 2025

Studies of Chaperone-Cochaperone Interactions using Homogenous Bead-Based Assay
06:51

Studies of Chaperone-Cochaperone Interactions using Homogenous Bead-Based Assay

Published on: July 21, 2021

2.9K

The use of pharmacological chaperones in rare diseases caused by reduced protein stability

Jon Gil-Martínez1, Ganeko Bernardo-Seisdedos2, José M Mato1,3

  • 1Precision Medicine and Metabolism Laboratory, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bizkaia, Spain.

Proteomics
|October 7, 2022
PubMed

Insights

Rare genetic diseases often stem from mutations causing unstable proteins. This review explores protein destabilization mechanisms and therapeutic strategies like pharmacological chaperones.

Area of Science:

  • Biochemistry and Molecular Biology
  • Genetics and Genomics
  • Pharmacology

Background:

  • Rare diseases are frequently caused by inherited genetic mutations leading to altered protein function.
  • Decreased protein stability, often due to missense mutations, is a primary mechanism, causing misfolded proteins and cellular dysfunction.
  • This can lead to the accumulation of toxic aggregates and impaired cellular homeostasis.

Purpose of the Study:

  • To review current knowledge on rare diseases linked to reduced protein stability.
  • To highlight the thermodynamic principles underlying protein destabilization in these conditions.
  • To discuss the potential of pharmacological chaperones as a therapeutic approach.

Main Methods:

  • Literature review of studies on rare diseases and protein stability.
  • Analysis of thermodynamic aspects of protein destabilization.
  • Examination of case studies involving pharmacological chaperone therapies.

Main Results:

  • Identified decreased protein stability as a common pathogenic mechanism in rare genetic disorders.
  • Emphasized the link between altered thermodynamic stability and cellular dysfunction.
  • Highlighted the emerging role of pharmacological chaperones in correcting protein misfolding and homeostasis.

Conclusions:

  • Rare diseases associated with protein instability represent a significant area of research.
  • Understanding the thermodynamics of protein destabilization is crucial for developing effective treatments.
  • Pharmacological chaperones show promise for treating these debilitating conditions by restoring protein function and cellular balance.
Keywords:
missense mutationpharmacological chaperonesprotein stabilityproteostasisrare diseases

More Related Videos

In Vitro Enzyme Measurement to Test Pharmacological Chaperone Responsiveness in Fabry and Pompe Disease10:16

In Vitro Enzyme Measurement to Test Pharmacological Chaperone Responsiveness in Fabry and Pompe Disease

Published on: December 20, 2017

8.2K
Using Caenorhabditis elegans to Screen for Tissue-Specific Chaperone Interactions06:55

Using Caenorhabditis elegans to Screen for Tissue-Specific Chaperone Interactions

Published on: June 7, 2020

3.0K

Related Concept Videos

Molecular Chaperones and Protein Folding03:00

Molecular Chaperones and Protein Folding

The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
The...
18.2K
Bacterial Protein Maturation01:26

Bacterial Protein Maturation

Bacterial protein maturation is a tightly regulated process that ensures newly synthesized polypeptides achieve correct functional conformations. This maturation involves a series of modifications, folding events, and quality control steps, often assisted by specialized chaperone proteins.N-Terminal ModificationsThe maturation of bacterial polypeptides begins cotranslationally as the polypeptide exits the ribosome. The first amino acid, N-formylmethionine (fMet), is typically modified at the...
69
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...
3.8K
Protein Folding Quality Check in the RER01:29

Protein Folding Quality Check in the RER

ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
3.8K
Protein Folding01:25

Protein Folding

Proteins are chains of amino acids linked together by peptide bonds. Upon synthesis, a protein folds into a three-dimensional conformation, critical to its biological function. Interactions between its constituent amino acids guide protein folding, and hence the protein structure is primarily dependent on its amino acid sequence.
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
8.4K
Factors Affecting Protein-Drug Binding: Patient-Related Factors01:29

Factors Affecting Protein-Drug Binding: Patient-Related Factors

Protein-drug binding, a pivotal aspect of pharmacokinetics, is subject to considerable variability influenced by an array of patient-related factors. The intricate interplay of age, individual differences, and pathological conditions significantly impact the binding dynamics and subsequent pharmacological effects.
Age stands as a key determinant in protein-drug binding. Neonates, characterized by low albumin content, experience heightened concentrations of unbound drugs such as phenytoin and...
104