Linking Ubiquitin Research to Drug Discovery

IDOL-E3 Ligase Assay

The E3 ubiquitin ligase Inducible Degrader of LDLR (IDOL) has recently been identified as a target of significant interest in Alzheimer’s Disease6 (AD). IDOL has a demonstrated a cellular role in the regulation and turnover of the LDL receptor (LDLR) in lipid homeostasis and to date has offered a route to the modulation of hypercholesterolaemia and cardiovascular disease1-5. Now, targeting IDOL provides a novel and exciting route to the modulation of apolipoprotein E- (ApoE) and β-amyloid- (Aβ) clearance in the brain offering potential therapeutic value in the treatment of AD6.

We have successfully developed one of the first commercially available assays to allow researchers to screen against IDOL in either HTS or non-HTS formats.

Our IDOL assay is now available to support research programmes with the objectives of identifying modulators of this putative drug target.  As with our other services, the assay can be configured in HTS or non-HTS formats depending on your requirements.

If you would like to learn more about our IDOL assay and discuss how it could be used to screen your compounds either email us at services@ubiquigent.com or please contact us here.

Why IDOL?

  • Loss of IDOL expression in transgenic mice increases brain LDLR, decreases ApoE, soluble and insoluble Aβ, reduces amyloid plaque burden and ameliorated neuroinflammation6
  • Targeting (down-regulating) IDOL-catalysed ubiquitylation of LDLR increases cell surface [LDLR] and LDL uptake, highlighting the potential value of this target in addressing Alzheimer’s Disease6 and cardiovascular disease4
  • The LDLR is essential for the uptake of LDL cholesterol and the regulation of plasma lipoprotein levels1
  • An inherited loss-of-function mutation in the LDLR gene in humans or poor diet can elevate plasma LDL levels, reduce LDL clearance and accelerate atherosclerosis and the risk of cardiovascular disease2,3
  • The E3 ligase IDOL is up-regulated by the sterol-activated transcription factors LXR alpha and LXR beta which increase IDOL expression resulting in ubiquitylation and subsequent degradation of the LDLR4,5

References

  1. Russell, D.W., W.J. Schneider, T. Yamamoto, K.L. Luskey, M.S. Brown, and J.L. Goldstein. 1984. Domain map of the LDL receptor: sequence homology with the epidermal growth factor precursor. Cell. 37:577-585.
  2. Brown, M.S., and J.L. Goldstein. 1986. A receptor-mediated pathway for cholesterol homeostasis. Science. 232:34-47.
  3. Tolleshaug, H., K.K. Hobgood, M.S. Brown, and J.L. Goldstein. 1983. The LDL receptor locus in familial hypercholesterolemia: multiple mutations disrupt transport and processing of a membrane receptor. Cell. 32:941-951.
  4. Zelcer, N., C. Hong, R. Boyadjian, and P. Tontonoz. 2009. LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science. 325:100-104.
  5. Zhang, L., L. Fairall, B.T. Goult, A.C. Calkin, C. Hong, C.J. Millard, P. Tontonoz, and J.W. Schwabe. 2011. The IDOL-UBE2D complex mediates sterol-dependent degradation of the LDL receptor. Genes Dev. 25:1262-1274.
  6. Choi J, Gao J, Kim J, Hong C, Kim J, Tontonoz P. 2015. The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis. Sci Transl Med. 7(314):314