Xie J, Guo Q.
PAR-4 is involved in regulation of beta-secretase cleavage of the Alzheimer amyloid precursor protein.
J Biol Chem. 2005 Apr 8;280(14):13824-32.
PubMed.
Factors that influence BACE activity are receiving increasing attention as it becomes clear that, compared to γ-secretase inhibition, BACE inhibition may be accomplished with relatively few side effects. In this paper, Jun Xie and Qing Guo expand on previous work indicating that Par-4 is elevated in AD and potentiates Aβ production upon neuronal insult. Here, they nicely show that the protein interacts directly with BACE and that Par-4 expression levels correlate with BACE activity and Aβ production.
As the authors note, Par-4 may exert its effect by several possible mechanisms. It will be interesting to determine whether Par-4 works by modulating the APP-BACE interaction or by some other mechanism. Since several studies have shown that co-trafficking of APP with BACE is a critical step leading to β-cleavage, the authors' idea that Par-4 influences BACE trafficking is particularly interesting to us. One readout for this might be to check whether Par-4 alters BACE maturation.
Altogether, this compelling study adds yet another protein to the increasing list of factors that are able to interact with, and modulate, BACE activity. The list so far includes reticulon family members, phospholipid scramblase 1, the copper chaperone for superoxide dismutase-1, and the brain-specific type II membrane protein BRI3 and GGA1. In addition to direct inhibition of BACE's catalytic site, altering BACE activity by targeting its binding partners might represent another possible therapeutic approach.
Comments
MassGeneral Institute for Neurodegenerative Diseases
Factors that influence BACE activity are receiving increasing attention as it becomes clear that, compared to γ-secretase inhibition, BACE inhibition may be accomplished with relatively few side effects. In this paper, Jun Xie and Qing Guo expand on previous work indicating that Par-4 is elevated in AD and potentiates Aβ production upon neuronal insult. Here, they nicely show that the protein interacts directly with BACE and that Par-4 expression levels correlate with BACE activity and Aβ production.
As the authors note, Par-4 may exert its effect by several possible mechanisms. It will be interesting to determine whether Par-4 works by modulating the APP-BACE interaction or by some other mechanism. Since several studies have shown that co-trafficking of APP with BACE is a critical step leading to β-cleavage, the authors' idea that Par-4 influences BACE trafficking is particularly interesting to us. One readout for this might be to check whether Par-4 alters BACE maturation.
Altogether, this compelling study adds yet another protein to the increasing list of factors that are able to interact with, and modulate, BACE activity. The list so far includes reticulon family members, phospholipid scramblase 1, the copper chaperone for superoxide dismutase-1, and the brain-specific type II membrane protein BRI3 and GGA1. In addition to direct inhibition of BACE's catalytic site, altering BACE activity by targeting its binding partners might represent another possible therapeutic approach.
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