In the January 7 PNAS, researchers from the biopharmaceutical company Scios Inc. reported that sumoylation, the covalent modification of lysine residues by small ubiquitin-like modifier (SUMO) proteins, has a dramatic impact on amyloid β production.
Working with principle investigator Barbara Cordell, first author Yonghong Li et al. discovered the sumoylation effect in a random screen of plasmids that can affect Aβ processing when transfected into human cells expressing Aβ precursor protein (AβPP). Of the roughly 100,000 plasmids harboring cDNA from human fetal brain tissue, one downregulated the expression of the N-terminal fragments produced by β-site cleavage of AβPP (β-NTF), and upregulated production of α-NTFs, the fragments produced by cleavage at the α-site. This plasmid turned out to code for SUMO-3.
When Li et al. further investigated this effect, they found a dose-response relationship between SUMO-3 and AβPP processing. At the highest doses of plasmid, Aβ production shrank by 25 percent, and there were concomitant increases and decreases in levels of α-NTF and β-NTF. In addition, dominant-negative mutants of SUMO-3 led to increased β-NTF and Aβ production, suggesting that endogenous SUMO-3 is involved in keeping these levels low.
While the connection between sumoylation and Aβ production is intriguing, this report raises many questions. For example, what substrates of SUMO-3 are involved in the regulation of AβPP processing? The authors show that neither the precursor, nor the enzyme responsible for the β-site cleavage (BACE), is sumoylated. They also show that SUMO-3 is present in hippocampal neurons and they hint at preliminary observations suggesting altered expression in Alzheimer's brains versus controls. To our knowledge, this is the first time sumoylation has been implicated directly in Alzheimer’s disease, however, there are prior reports suggesting that this form of post-translational protein modification plays a role in polyglutamine repeat diseases (Ueda et al., 2002; Chan et al., 2002).—Tom Fagan
- Ueda H, Goto J, Hashida H, Lin X, Oyanagi K, Kawano H, Zoghbi HY, Kanazawa I, Okazawa H. Enhanced SUMOylation in polyglutamine diseases. Biochem Biophys Res Commun. 2002 Apr 26;293(1):307-13. PubMed.
- Chan HY, Warrick JM, Andriola I, Merry D, Bonini NM. Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila. Hum Mol Genet. 2002 Nov 1;11(23):2895-904. PubMed.
No Available Further Reading
- Li Y, Wang H, Wang S, Quon D, Liu YW, Cordell B. Positive and negative regulation of APP amyloidogenesis by sumoylation. Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):259-64. PubMed.