Also, binding of Zn(II) and Cu(II) by GMP-1 is weaker than the 8-hydroxyquinoline scaffold compound clioquinol previously tested in AD clinical trials.
The opposite effect of Aβ and oxidative/excitotoxic stimuli on SUMO1 modification may cause the pathological stage-associated change in the level of SUMO-modified proteins in the AD mouse brain.
Development of GMP-1 a molecular chaperone network modulator protecting mitochondrial function and its assessment in fly and mice models of Alzheimer's disease.
We found that rs12472035 polymorphism of SUMO1 was significantly associated with an increased risk of AD in male group (the CT genotype of rs12472035: adjusted OR=8.737, 95% CI=2.041-37.41, p-value=0.003).
We show that tau SUMOylation induces tau hyperphosphorylation at multiple AD-associated sites, whereas site-specific mutagenesis of tau at K340R (the SUMOylation site) or simultaneous inhibition of tau SUMOylation by ginkgolic acid abolishes the effect of small ubiquitin-like modifier protein 1 (SUMO-1).
Our study indicates SUMO1 is not only a novel and potent regulator of BACE1 accumulation and Aβ generation but also a potential therapeutic target for Alzheimer's disease.
Further, overexpression of the SUMO E2 enzyme ubc9 along with SUMO-1 results in decreased levels of Abeta 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.