Sumoylation of amyloid precursor protein negatively regulates Aβ aggregate levels

Yu Qian Zhang, Kevin D. Sarge

Research output: Contribution to journalArticlepeer-review

83 Citations (SciVal)

Abstract

The proteolytic processing of amyloid precursor protein (APP) to produce Aβ peptides is thought to play an important role in the mechanism of Alzheimer's disease. Here, we show that lysines 587 and 595 of APP, which are immediately adjacent to the site of β-secretase cleavage, are covalently modified by SUMO proteins in vivo. Sumoylation of these lysine residues is associated with decreased levels of Aβ aggregates. Further, overexpression of the SUMO E2 enzyme ubc9 along with SUMO-1 results in decreased levels of Aβ aggregates in cells transfected with the familial Alzheimer's disease-associated V642F mutant APP, indicating the potential of up-regulating activity of the cellular sumoylation machinery as an approach against Alzheimer's disease. The results also provide the first demonstration that the SUMO E2 enzyme (ubc9) is present within the endoplasmic reticulum, indicating how APP, and perhaps other proteins that enter this compartment, can be sumoylated.

Original languageEnglish
Pages (from-to)673-678
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume374
Issue number4
DOIs
StatePublished - Oct 3 2008

Bibliographical note

Funding Information:
We are grateful to Dr. Iliya Lefterov for the pCITE-4a (+)-APP 695 plasmid, Dr. Kim Orth for the HA-SUMO-1/HA-SUMO-2 expression plasmids, Dr. Paul Murphy for the pAG3-His-APPΔNL plasmid, Dr. Moshe Sadofsky for the pcDNA3-ubc9 plasmid, Dr. Jeff Rush and Dr. Skip Waechter for calf-brain microsomes and anti-calnexin antibody, and to Dr. Louis Hersh and Dr. Doug Andres for gifts of antibodies. This research was supported by NIH Grant GM64606 to K.D.S.

Keywords

  • APP
  • Alzheimer's
  • SUMO-1
  • SUMO-2
  • Ubc9

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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