Par-4—Not a Long Shot to BACE

Par-4, the leucine-zipper protein first found in apoptotic prostate cancer cells, can regulate β-secretase (BACE) cleavage of amyloid-β precursor protein (AβPP), according to a paper in press in the January 25 Journal of Biological Chemistry. The new finding could explain, partly at least, why BACE activity (see ARF related news story), and, therefore, amyloid-β production are elevated in AD.

Qing Guo and colleagues have previously shown that Par-4 is elevated in brain tissue from Alzheimer disease (AD) patients (see Guo et al., 1998) and that it causes increased production of Aβ1-42 in neurons challenged with apoptotic stimuli (see Guo and Xie, 2004). To test if Par-4 can affect BACE cleavage of AβPP directly, first author Jun Xie, working with Guo at the University of Oklahoma Health Sciences Center, cotransfected both proteins into neuroblastoma cells. The authors found that in the presence of Par-4, BACE cleavage of AβPP was significantly increased (about 1.5-fold), while production of Aβ1-42 rose about twofold. When Xie immunoprecipitated BACE1 from neuroblastoma cells overexpressing both proteins, he found that Par-4 co-purified with the protease. Taken together, the two sets of experiments suggest that Par-4 interacts with BACE to increase cleavage of AβPP and accelerate production of Aβ1-42. To confirm the physiological relevance of this, the authors used antibodies to isolate the proteins from primary hippocampal neurons, finding that BACE/Par-4 coprecipitated from these cells also.

While Par-4 is a cytosolic protein, BACE is membrane-bound, having a short cytoplasmic tail that sticks into the cell cytoplasm. If Par-4 and BACE were to interact directly, it would most likely be via this cytoplasmic tail. To test this, Xie made an affinity column using the BACE tail peptide, and tested to see if it could capture Par-4. While this method did reel in full-length Par-4, it failed to capture the protein if the C-terminal half was deleted. This suggests that BACE and Par-4 can directly interact through their C-terminal ends.

"The identification of Par-4 as an endogenous regulator of BACE1 activity may have significant implications for developing novel therapeutic strategies for AD,” write the authors. And, indeed, they showed that knocking down Par-4 using RNAi reduced BACE cleavage of wild-type AβPP by over twofold, and AβPP harboring mutations found in some familial forms of AD (the so-called Swedish and Indiana mutations) by almost threefold. The scope of Par-4 studies may not end with AD, however. The authors also recently reported that RNAi-mediated silencing of Par-4 can protect neurons and synaptosomes isolated from mice that model amyotrophic lateral sclerosis (see Xie et al., 2005).—Tom Fagan

Comments

  1. 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.

    View all comments by Christine A.F. von Arnim

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References

News Citations

  1. Follow the BACE to Higher Aβ Levels

Paper Citations

  1. Guo Q, Fu W, Xie J, Luo H, Sells SF, Geddes JW, Bondada V, Rangnekar VM, Mattson MP. Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease. Nat Med. 1998 Aug;4(8):957-62. PubMed.
  2. Guo Q, Xie J. AATF inhibits aberrant production of amyloid beta peptide 1-42 by interacting directly with Par-4. J Biol Chem. 2004 Feb 6;279(6):4596-603. PubMed.
  3. Xie J, Awad KS, Guo Q. RNAi knockdown of Par-4 inhibits neurosynaptic degeneration in ALS-linked mice. J Neurochem. 2005 Jan;92(1):59-71. PubMed.

Further Reading

No Available Further Reading

Primary Papers

  1. 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.

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