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Бобрышева, И. В.; Grigorenko, Anastasia P.; Новосадова, Е. В.; Kal'ina, N. R.; Arsenyeva, E. L.; Гривенников, И. А.; Tarantul, V. Z.; Rogaev, Evgeny I.

doi:10.1023/a:1024605523743

Cited by 2 publications

(2 citation statements)

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“…We observed similar weak inhibitory effects of the various mutations in less conserved and AD-related amino acid positions (Figure 2 ). As previously described, AD-associated C410Y mutation led to a strong inhibition of PSEN1 processing (Figure 2 ) [ 64 , 65 ].…”

Section: Resultssupporting

confidence: 57%

“…Mutations in the “presenilinase” cleavage site (PSEN1 M292D, M292E) strongly inhibit the autocleavage while the AD-related PSEN1ΔE9 mutation completely abolishes PSEN1 endoproteolysis, although in both cases γ-secretase remains active [ 59 , 62 ]. Variable inhibitory effects on PSEN1 processing have been described for different AD-associated mutations [ 63 – 65 ].…”

Section: Resultsmentioning

confidence: 99%

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Mutational re-modeling of di-aspartyl intramembrane proteases: uncoupling physiologically-relevant activities from those associated with Alzheimer’s disease

et al. 2017

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The intramembrane proteolytic activities of presenilins (PSEN1/PS1 and PSEN2/ PS2) underlie production of β-amyloid, the key process in Alzheimer's disease (AD). Dysregulation of presenilin-mediated signaling is linked to cancers. Inhibition of the γ-cleavage activities of PSENs that produce Aβ, but not the ε-like cleavage activity that release physiologically essential transcription activators, is a potential approach for the development of rational therapies for AD. In order to identify whether different activities of PSEN1 can be dissociated, we designed multiple mutations in the evolutionary conserved sites of PSEN1. We tested them in vitro and in vivo assays and compared their activities with mutant isoforms of presenilin-related intramembrane di-aspartyl protease (IMPAS1 (IMP1)/signal peptide peptidase (SPP)). PSEN1 autocleavage was more resistant to the mutation remodeling than the ε-like proteolysis. PSEN1 with a G382A or a P433A mutation in evolutionary invariant sites retains functionally important APP ε-and Notch S3-cleavage activities, but G382A inhibits APP γ-cleavage and Aβ production and a P433A elevates Aβ. The G382A variant cannot restore the normal cellular ER Ca 2+ leak in PSEN1/PSEN2 double knockout cells, but efficiently rescues the loss-of-function (Egl) phenotype of presenilin in C. elegans. We found that, unlike in PSEN1 knockout cells, endoplasmic reticulum (ER) Ca 2+ leak is not changed in the absence of IMP1/SPP. IMP1/SPP with the analogous mutations retained efficiency in cleavage of transmembrane substrates and rescued the lethality of Ce-imp-2 knockouts. In summary, our data show that mutations near the active catalytic sites of intramembrane di-aspartyl proteases have different consequences on proteolytic and signaling functions. www.impactjournals.com/oncotarget/

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Section: Resultssupporting

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Mutational re-modeling of di-aspartyl intramembrane proteases: uncoupling physiologically-relevant activities from those associated with Alzheimer’s disease

et al. 2017

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Similar effects of mouse and human <i>pub</i> gene on proliferation and embryoid bodies formation in mouse embryonic stem cells <i>in vitro</i>

Новосадова¹,

Khaydarova²,

Manuilova³

et al. 2012

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Previously we have demonstrated that pub gene modulates expression of PU.1 transcription factor and plays an important role in differentiation of embryonic stem cells not only at early stages (during formation of embryoid bodies), but also during differentiation into ectodermal, mesodermal and endodermal derivatives in vitro. We have compared the influence of elevated expression of two homological genes mpub and hpub of mouse and human respectively on early stages of differentiation of murine embryonic stem cells. Overexpression of both genes caused an increase in the number of formed embryoid bodies but did not alter the proliferative activity of transfected embryonic stem cells. It was also observed that expression of mpub and hpub led to decreased expression of pu.1 mRNA.

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Cited by 2 publications

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Mutational re-modeling of di-aspartyl intramembrane proteases: uncoupling physiologically-relevant activities from those associated with Alzheimer’s disease

Mutational re-modeling of di-aspartyl intramembrane proteases: uncoupling physiologically-relevant activities from those associated with Alzheimer’s disease

Similar effects of mouse and human <i>pub</i> gene on proliferation and embryoid bodies formation in mouse embryonic stem cells <i>in vitro</i>

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Cited by 2 publications

References 11 publications

Mutational re-modeling of di-aspartyl intramembrane proteases: uncoupling physiologically-relevant activities from those associated with Alzheimer’s disease

Mutational re-modeling of di-aspartyl intramembrane proteases: uncoupling physiologically-relevant activities from those associated with Alzheimer’s disease

Similar effects of mouse and human &lt;i&gt;pub&lt;/i&gt; gene on proliferation and embryoid bodies formation in mouse embryonic stem cells &lt;i&gt;in vitro&lt;/i&gt;

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Similar effects of mouse and human <i>pub</i> gene on proliferation and embryoid bodies formation in mouse embryonic stem cells <i>in vitro</i>