Novel Domain of LRP Cytoplasmic Tail in APP Processing
Dr. David Kang and collaborators recently found that a protein called LRP normally promotes generation of toxic beta-amyloid protein by moving its precursor protein, called APP, inside cells into compartments where the “molecular scissors” are most active. More than 80% of beta-amyloid production is dependent on the presence of LRP protein. However, the specific cause of this increased LRP-mediated transport and APP processing is unknown.
With the support of this BrightFocus award, Dr. Kang and collaborators discovered that a very small region of LRP (called LRP-C37) by itself is sufficient to mimic LRP's ability to increase generation of beta-amyloid. More specifically, they found that certain parts of the LRP-C37 region dictate how much beta-amyloid is produced. In addition, they identified a new scaffolding protein, called RanBP9, which physically interacts with LRP-C37 to modify the cuts made in APP. This is an important finding, because RanBP9 is increased in the brains of individuals with Alzheimer's disease. Therefore, RanBP9 is responsible for directing APP transport to domains inside cells where the “molecular scissors” are most active. Blocking the LRP-RanBP9 interaction might be a new and attractive way of therapeutically stemming beta-amyloid production, and the resulting nerve cell damage, in Alzheimer's disease.
Lakshmana MK, Yoon IS, Chen E, Bianchi E, Koo EH, Kang DE. (2009). Novel role of RanBP9 in BACE1 processing of amyloid precursor protein and amyloid beta peptide generation. J. Biol. Chem. 284(18):11863-72.
Lakshmana MK, Chung JY, Wickramarachchi S, Tak E, Bianchi E, Koo EH, Kang DE. (2010). A fragment of the scaffolding protein RanBP9 is increased in Alzheimer's disease brains and strongly potentiates amyloid-beta peptide generation. FASEB J. 24(1):119-27.
Boo JH, Song H, Kim JE, Kang DE, Mook-Jung I. (2009). Accumulation of phosphorylated beta-catenin enhances ROS-induced cell death in presenilin-deficient cells. PLoS One. 2009;4(1):e4172. Epub 2009 Jan 12.
Cheung KH, Mei L, Mak DO, Hayashi I, Iwatsubo T, Kang DE, Foskett JK. (2010). Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer's disease-linked presenilin mutants in human cells and mouse neurons. Sci Signal. 2010 Mar 23;3(114):ra22.
First published on: June 10, 2008
Last modified on: April 7, 2011