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?-arrestin1 regulates ?-secretase complex assembly and modulates amyloid-? pathology.

ABSTRACT: Alzheimer's disease (AD) is a progressive and complex neurodegenerative disease in which the ?-secretase-mediated amyloid-? (A?) pathology plays an important role. We found that a multifunctional protein, ?-arrestin1, facilitated the formation of NCT/APH-1 (anterior pharynx-defective phenotype 1) precomplex and mature ?-secretase complex through its functional interaction with APH-1. Deficiency of ?-arrestin1 or inhibition of binding of ?-arrestin1 with APH-1 by small peptides reduced A? production without affecting Notch processing. Genetic ablation of ?-arrestin1 diminished A? pathology and behavioral deficits in transgenic AD mice. Moreover, in brains of sporadic AD patients and transgenic AD mice, the expression of ?-arrestin1 was upregulated and correlated well with neuropathological severity and senile A? plaques. Thus, our study identifies a regulatory mechanism underlying both ?-secretase assembly and AD pathogenesis, and indicates that specific reduction of A? pathology can be achieved by regulation of the ?-secretase assembly.

SUBMITTER: Liu X

PROVIDER: S-EPMC3587707 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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β-arrestin1 regulates γ-secretase complex assembly and modulates amyloid-β pathology.

Liu Xiaosong X Zhao Xiaohui X Zeng Xianglu X Bossers Koen K Swaab Dick F DF Zhao Jian J Pei Gang G

Cell research 20121204 3

Alzheimer's disease (AD) is a progressive and complex neurodegenerative disease in which the γ-secretase-mediated amyloid-β (Aβ) pathology plays an important role. We found that a multifunctional protein, β-arrestin1, facilitated the formation of NCT/APH-1 (anterior pharynx-defective phenotype 1) precomplex and mature γ-secretase complex through its functional interaction with APH-1. Deficiency of β-arrestin1 or inhibition of binding of β-arrestin1 with APH-1 by small peptides reduced Aβ product ...[more]

PMID: 23208420

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Project description:Mutations in presenilin proteins (PS1 and PS2) lead to early-onset Alzheimer's disease. PS proteins are endoproteolytically cleaved into two main fragments: the NTF (PS N-terminal fragment) and the CTF (PS C-terminal fragment). The two fragments are believed to constitute the core catalytic enzyme activity called gamma-secretase, which is responsible for cleaving beta-amyloid precursor protein to release Abeta. Thus, studying factors that modulate PS fragment levels could provide important information about gamma-secretase. Previously, we demonstrated that the protein, ubiquilin-1, interacts both in vivo and in vitro with PS and that overexpression of ubiquilin-1 or -2 leads to increased accumulation of full-length PS proteins. Using wild-type HEK-293 cells (human embryonic kidney 293 cells) and PS-inducible cells, we now show that overexpression of either ubiquilin-1 or -2 decreases the PS NTF and CTF levels. Conversely, siRNA (small interfering RNA)-mediated knockdown of ubiquilin-1 and -2 proteins increased the PS NTF and CTF levels. We considered that ubiquilin might alter PS fragment accumulation by acting as a shuttle factor escorting PS fragments to the proteasome for degradation. However, through proteasome inhibition studies, we show that this does not occur. Instead, our results suggest that ubiquilin regulates PS fragment production. We also examined whether other components of the gamma-secretase complex are affected by ubiquilin expression. Interestingly, overexpression of ubiquilin resulted in a decrease in Pen-2 and nicastrin levels, two essential components of the gamma-secretase complex. In contrast, knockdown of ubiquilin-1 and -2 protein expression by RNAi (RNA interference) increased Pen-2 and nicastrin levels. Finally, we show that inhibition of the proteasome results in decreased PS fragment production and that reversal of proteasome inhibition restores PS fragment production, suggesting that the proteasome may be involved in PS endoproteolysis. These studies implicate ubiquilin as an important factor in regulating PS biogenesis and metabolism.

Dataset Information

?-arrestin1 regulates ?-secretase complex assembly and modulates amyloid-? pathology.

Publications

β-arrestin1 regulates γ-secretase complex assembly and modulates amyloid-β pathology.

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