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| Presenilin: Showing less cleavage
Presenilin: Showing less cleavage Presenilin proteins are found in highly stable protein complexes and are essential for γ-secretase and ε-secretase cleavage of type 1 transmembrane proteins such as amyloid precursor protein (APP), Notch and cadherins. γ-site cleavage of APP is responsible for the generation of amyloid-ß peptide which is thought to be causal for both the pathology of Alzheimer's disease and the subsequent cognitive decline. This week in Nature, Paul Fraser and colleagues show that TMP21, a member of the p24 cargo protein family, is a novel presenilin complex component that specifically regulates γ-secretase activity.
Presenilins have been shown to interact with nicastrin, aph-1 and pen-2, but the molecular weight of isolated presenilin complexes suggests that additional components may also exist. Fraser and colleagues analyzed by mass spectrometry the tryptic protein fragments of immunopurified blastocyst-derived presenilin 1 complexes and identified the p24 protein cargo family member TMP21. In agreement with this finding, both endogenous and overexpressed TMP21 co-precipitate with components of the presenilin complex in HEK293 cells and mouse brain. To determine the function of TMP21 in presenilin complexes, the authors assessed the effects of TMP21 expression on secretase activity. Whereas overexpression had no significant effect, TMP21 suppression by small interfering RNA (siRNA) lead to a dramatic increase in amyloid-ß peptide production. TMP21 has previously been shown to regulate protein transport and quality control, but reduction of TMP21 expression did not affect complex assembly or substrate trafficking. TMP21 may instead act as a direct modulator of the presenilin complex. Indeed, addition of exogenous TMP21 to purified TMP21-deficient PS1 complexes reverts γ-secretase activity to the levels observed in wild type complexes. Notably, TMP21 downregulation by siRNA did not affect ε-secretase cleavage - as measured by the production of the intracellular domains of amyloid, Notch and cadherin - indicating that TMP21 specifically modulates presenilin dependent γ-site cleavage. This paper demonstrates for the first time that γ- and ε-site cleavage are independently regulated. The precise mechanism by which TMP21 decreases the γ-secretase activity of presenilin complexes remains to be elucidated, but future studies may shed light on whether specific manipulation of γ-site cleavage is a useful strategy for the treatment of Alzheimer's disease. Monica Hoyos-Flight
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