Dynamic Nature of presenilin1/γ-Secretase: Implication for Alzheimer's Disease Pathogenesis.
Presenilin 1 (PS1) is a catalytic component of the γ-secretase complex, responsible for the intramembraneous cleavage of more than 90 type I transmembrane proteins, including Alzheimer's disease (AD)-related amyloid precursor protein (APP). The γ-secretase-mediated cleavage of the APP C-terminal membrane stub leads to the production of various amyloid β (Aβ) species. The assembly of Aβ into neurotoxic oligomers, which causes synaptic dysfunction and neurodegeneration, is influenced by the relative ratio of the longer (Aβ42/43) to shorter Aβ (Aβ40) peptides. The ratio of Aβ42 to Aβ40 depends on the conformation and activity of the PS1/γ-secretase enzymatic complex. The latter exists in a dynamic equilibrium of the so called "closed" and "open" conformational states, as determined by the Förster resonance energy transfer (FRET)-based PS1 conformation assay. Here we review several factors that can allosterically influence conformational status of the enzyme, and hence the production of Aβ peptides. These include genetic variations in PS1, APP and other γ-secretase components, environmental stressors implicated in AD pathogenesis and pharmacological agents. Since "closed" PS1 conformation is the common outcome of many AD-related insults, the novel assays monitoring PS1 conformation in live/intact cells in vivo and in vitro might be utilized for diagnostic purposes and for validation of the potential therapeutic approaches.
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA, 02129, USA. kzoltowska@mgh.harvard.edu.
Katarzyna Marta
KM
Zoltowska
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA, 02129, USA. oberezovska@mgh.harvard.edu.
Oksana
O
Berezovska
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D006801:Humans; D009154:Mutation / Q000502:physiology; D053764:Presenilin-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation
D016229:Amyloid beta-Peptides; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases
Alzheimer’s disease; Amyloid β; Presenilin 1; γ-secretase