Neurodegenerative diseases associated with the disruption of proteostasis and their therapeutic strategies using chemical chaperones

J Biochem. 2024 Sep 3;176(3):179-186. doi: 10.1093/jb/mvae048.

Abstract

Aberrant proteostasis is thought to be involved in the pathogenesis of neurodegenerative diseases. Some proteostasis abnormalities are ameliorated by chaperones. Chaperones are divided into three groups: molecular, pharmacological and chemical. Chemical chaperones intended to alleviate stress in organelles, such as the endoplasmic reticulum (ER), are now being administered clinically. Of the chemical chaperones, 4-phenylbutyrate (4-PBA) has been used as a research reagent, and its mechanism of action includes chaperone effects and the inhibition of histone deacetylase. Moreover, it also binds to the B-site of SEC24 and regulates COPII-mediated transport from the ER. Although its therapeutic effect may not be strong, elucidating the mechanism of action of 4-PBA may contribute to the identification of novel therapeutic targets for neurodegenerative diseases.

Keywords: 4-PBA; COPII vesicles; chaperone; endoplasmic reticulum; neurodegenerative diseases.

Publication types

  • Review

MeSH terms

  • Animals
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Molecular Chaperones* / metabolism
  • Neurodegenerative Diseases* / drug therapy
  • Neurodegenerative Diseases* / metabolism
  • Phenylbutyrates* / pharmacology
  • Phenylbutyrates* / therapeutic use
  • Proteostasis* / drug effects

Substances

  • Molecular Chaperones
  • Phenylbutyrates
  • 4-phenylbutyric acid