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

Autor:	Grigorenko AP; Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604, USA.; Department of Genomics and Human Genetics, Institute of General Genetics, Russian Academy of Sciences, Moscow, 119991 Russia.; Center for Brain Neurobiology and Neurogenetics, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia., Moliaka YK; Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604, USA., Plotnikova OV; Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604, USA., Smirnov A; Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604, USA., Nikishina VA; Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604, USA., Goltsov AY; Department of Genomics and Human Genetics, Institute of General Genetics, Russian Academy of Sciences, Moscow, 119991 Russia.; Center for Brain Neurobiology and Neurogenetics, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia., Gusev F; Department of Genomics and Human Genetics, Institute of General Genetics, Russian Academy of Sciences, Moscow, 119991 Russia.; Center for Brain Neurobiology and Neurogenetics, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia., Andreeva TV; Department of Genomics and Human Genetics, Institute of General Genetics, Russian Academy of Sciences, Moscow, 119991 Russia.; Center for Brain Neurobiology and Neurogenetics, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia., Nelson O; Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9040, USA., Bezprozvanny I; Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9040, USA., Rogaev EI; Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604, USA.; Department of Genomics and Human Genetics, Institute of General Genetics, Russian Academy of Sciences, Moscow, 119991 Russia.; Center for Brain Neurobiology and Neurogenetics, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia.; Center for Genetics and Genetic Technologies, Faculty of Biology, Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, 119234, Russia.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2017 May 30; Vol. 8 (47), pp. 82006-82026. Date of Electronic Publication: 2017 May 30 (Print Publication: 2017).
DOI:	10.18632/oncotarget.18299
Abstrakt:	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 auto-cleavage 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. Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to disclose.
Databáze:	MEDLINE
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