TTC3-Mediated Protein Quality Control, A Potential Mechanism for Cognitive Impairment

Cell Mol Neurobiol. 2022 Aug;42(6):1659-1669. doi: 10.1007/s10571-021-01060-z. Epub 2021 Feb 27.

Abstract

The tetrapeptide repeat domain 3 (TTC3) gene falls within Down's syndrome (DS) critical region. Cognitive impairment is a common phenotype of DS and Alzheimer's disease (AD), and overexpression of TTC3 can accelerate cognitive decline, but the specific mechanism is unknown. The TTC3-mediated protein quality control (PQC) mechanism, similar to the PQC system, is divided into three parts: it acts as a cochaperone to assist proteins in folding correctly; it acts as an E3 ubiquitin ligase (E3s) involved in protein degradation processes through the ubiquitin-proteasome system (UPS); and it may also eventually cause autophagy by affecting mitochondrial function. Thus, this article reviews the research progress on the structure, function, and metabolism of TTC3, including the recent research progress on TTC3 in DS and AD; the role of TTC3 in cognitive impairment through PQC in combination with the abovementioned attributes of TTC3; and the potential targets of TTC3 in the treatment of such diseases.

Keywords: Cognitive impairment; Down’s syndrome; E3 ubiquitin ligase; Protein quality control; TTC3.

Publication types

  • Review

MeSH terms

  • Alzheimer Disease / genetics
  • Cognitive Dysfunction* / genetics
  • Down Syndrome / genetics
  • Humans
  • Proteasome Endopeptidase Complex / metabolism
  • Ubiquitin-Protein Ligases* / genetics
  • Ubiquitin-Protein Ligases* / metabolism

Substances

  • TTC3 protein, human
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex

Supplementary concepts

  • Down Syndrome Critical Region