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Development (Cambridge, England) May 2022Recent evidence has shown that presenilin enhancer 2 (Pen2; Psenen) plays an essential role in corticogenesis by regulating the switch of apical progenitors (APs) to...
Recent evidence has shown that presenilin enhancer 2 (Pen2; Psenen) plays an essential role in corticogenesis by regulating the switch of apical progenitors (APs) to basal progenitors (BPs). The hippocampus is a brain structure required for advanced functions, including spatial navigation, learning and memory. However, it remains unknown whether Pen2 is important for hippocampal morphogenesis. To address this question, we generated Pen2 conditional knockout (cKO) mice, in which Pen2 is inactivated in neural progenitor cells (NPCs) in the hippocampal primordium. We showed that Pen2 cKO mice exhibited hippocampal malformation and decreased population of NPCs in the neuroepithelium of the hippocampus. We found that deletion of Pen2 neither affected the proliferative capability of APs nor the switch of APs to BPs in the hippocampus, and that it caused enhanced transition of APs to neurons. We demonstrated that expression of the Notch1 intracellular domain (N1ICD) significantly increased the population of NPCs in the Pen2 cKO hippocampus. Collectively, this study uncovers a crucial role for Pen2 in the maintenance of NPCs during hippocampal development.
Topics: Animals; Hippocampus; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurogenesis; Neurons; Presenilins
PubMed: 35575074
DOI: 10.1242/dev.200272 -
Trends in Pharmacological Sciences Nov 1996
Review
Topics: Alzheimer Disease; Binding Sites; Humans; Membrane Proteins; Models, Molecular; Mutation; Presenilin-1; Presenilin-2
PubMed: 8990952
DOI: 10.1016/s0165-6147(96)40003-7 -
Biological Chemistry Aug 2010Presenilin is the catalytic component of gamma-secretase, a complex aspartyl protease and a founding member of intramembrane-cleaving proteases. gamma-Secretase is... (Review)
Review
Presenilin is the catalytic component of gamma-secretase, a complex aspartyl protease and a founding member of intramembrane-cleaving proteases. gamma-Secretase is involved in the pathogenesis of Alzheimer's disease and a top target for therapeutic intervention. However, the protease complex processes a variety of transmembrane substrates, including the Notch receptor, raising concerns about toxicity. Nevertheless, gamma-secretase inhibitors and modulators have been identified that allow Notch processing and signaling to continue, and promising compounds are entering clinical trials. Molecular and biochemical studies offer a model for how this protease hydrolyzes transmembrane domains in the confines of the lipid bilayer. Progress has also been made toward structure elucidation of presenilin and the gamma-secretase complex by electron microscopy as well as by studying cysteine-mutant presenilins. The signal peptide peptidase (SPP) family of proteases are distantly related to presenilins. However, the SPPs work as single polypeptides without the need for cofactors and otherwise appear to be simple model systems for presenilin in the gamma-secretase complex. SPP biology, structure, and inhibition will also be discussed.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Humans; Presenilins; Protease Inhibitors; Protein Structure, Tertiary; Receptors, Notch; Signal Transduction; Substrate Specificity
PubMed: 20482315
DOI: 10.1515/BC.2010.086 -
Schizophrenia Research Aug 2023
Review
Impaired calcium channel function and pronounced hippocampal atrophy in a schizophrenia patient with cognitive impairment carrying Presenilin-2 Ser130Leu mutation: A case report and literature review.
Topics: Humans; Calcium Channels; Schizophrenia; Presenilin-2; Mutation; Cognitive Dysfunction; Hippocampus; Atrophy; Presenilin-1; Magnetic Resonance Imaging
PubMed: 37517367
DOI: 10.1016/j.schres.2023.07.024 -
EMBO Reports Feb 2007Presenilin mutations are the main cause of familial Alzheimer disease. From a genetic point of view, these mutations seem to result in a gain of toxic function; however,... (Review)
Review
Presenilin mutations are the main cause of familial Alzheimer disease. From a genetic point of view, these mutations seem to result in a gain of toxic function; however, biochemically, they result in a partial loss of function in the gamma-secretase complex, which affects several downstream signalling pathways. Consequently, the current genetic terminology is misleading. In fact, the available data indicate that several clinical presenilin mutations also lead to a decrease in amyloid precursor protein-derived amyloid beta-peptide generation, further implying that presenilin mutations are indeed loss-of-function mutations. The loss of function of presenilin causes incomplete digestion of the amyloid beta-peptide and might contribute to an increased vulnerability of the brain, thereby explaining the early onset of the inherited form of Alzheimer disease. In this review, I evaluate the implications of this model for the amyloid-cascade hypothesis and for the efficacy of presenilin/gamma-secretase as a drug target.
Topics: Alzheimer Disease; Amino Acid Sequence; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Humans; Models, Biological; Molecular Sequence Data; Mutation; Peptide Fragments; Presenilins; Protein Conformation
PubMed: 17268505
DOI: 10.1038/sj.embor.7400897 -
Cell Death and Differentiation Nov 2022Mutations in presenilin 1 and 2 (PS1 and PS2) cause autosomal dominant familial Alzheimer's disease (FAD). Ferroptosis has been implicated as a mechanism of...
Mutations in presenilin 1 and 2 (PS1 and PS2) cause autosomal dominant familial Alzheimer's disease (FAD). Ferroptosis has been implicated as a mechanism of neurodegeneration in AD since neocortical iron burden predicts Alzheimer's disease (AD) progression. We found that loss of the presenilins dramatically sensitizes multiple cell types to ferroptosis, but not apoptosis. FAD causal mutations of presenilins similarly sensitizes cells to ferroptosis. The presenilins promote the expression of GPX4, the selenoprotein checkpoint enzyme that blocks ferroptosis by quenching the membrane propagation of lethal hydroperoxyl radicals. Presenilin γ-secretase activity cleaves Notch-1 to signal LRP8 expression, which then controls GPX4 expression by regulating the supply of selenium into the cell since LRP8 is the uptake receptor for selenoprotein P. Selenium uptake is thus disrupted by presenilin FAD mutations, suppressing GPX4 expression. Therefore, presenilin mutations may promote neurodegeneration by derepressing ferroptosis, which has implications for disease-modifying therapeutics.
Topics: Humans; Alzheimer Disease; Amyloid Precursor Protein Secretases; Ferroptosis; Mutation; Presenilin-1; Presenilins; Selenium
PubMed: 35449212
DOI: 10.1038/s41418-022-01003-1 -
Cellular Signalling Sep 2003Presenilins (PS) constitute a fascinating family of proteins that play crucial roles in several major signalling processes involved in key cellular functions and are... (Review)
Review
Presenilins (PS) constitute a fascinating family of proteins that play crucial roles in several major signalling processes involved in key cellular functions and are also closely associated with dysfunction in Alzheimer's disease (AD). Presenilin-dependent intramembrane cleavage of transmembrane proteins such as amyloid beta precursor protein (AbetaPP) and Notch resides in a high-molecular-weight gamma-secretase protein complex, of which at least five core components have now been identified. Remarkably, it has now become evident that presenilin-dependent gamma-secretase activity extends beyond its role in AbetaPP and Notch cleavages to have a generic role in the regulated intramembranous cleavage of certain membrane proteins. Actually, a new picture is emerging in which cells can relay signals from the extracellular space to their interior through presenilin-dependent proteolysis within the membrane-spanning regions of type 1 integral membrane proteins to generate potential transcriptionally active intracellular fragments. This review deals with the complex biology of presenilins and focuses more specifically on recent developments regarding the composition, assembly and regulation of the gamma-secretase protein complex, its substrates and its implications for cellular signalling.
Topics: Amino Acid Sequence; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Binding Sites; Endopeptidases; Humans; Macromolecular Substances; Membrane Proteins; Models, Biological; Molecular Sequence Data; Presenilin-1; Presenilin-2; Sequence Homology, Amino Acid; Signal Transduction; Substrate Specificity
PubMed: 12834808
DOI: 10.1016/s0898-6568(03)00041-x -
Neuro-degenerative Diseases 2007To date the most relevant role for the amyloid precursor protein (APP) and for the presenilins (PSs) on Alzheimer's disease (AD) genesis is linked to the 'amyloid... (Review)
Review
To date the most relevant role for the amyloid precursor protein (APP) and for the presenilins (PSs) on Alzheimer's disease (AD) genesis is linked to the 'amyloid hypothesis', which considers an aberrant formation of amyloid-beta peptides the cause of neurodegeneration. In this view, APP is merely a substrate, cleaved by the gamma-secretase complex to form toxic amyloid peptides, PSs are key players in gamma-secretase complex, and corollary or secondary events are Tau-linked pathology and gliosis. A second theory, complementary to the amyloid hypothesis, proposes that APP and PSs may modulate a yet unclear cell signal, the disruption of which may induce cell-cycle abnormalities, neuronal death, eventually amyloid formation and finally dementia. This hypothesis is supported by the presence of a complex network of proteins, with a clear relevance for signal transduction mechanisms, which interact with APP or PSs. In this scenario, the C-terminal domain of APP has a pivotal role due to the presence of the 682YENPTY687 motif that represents the docking site for multiple interacting proteins involved in cell signaling. In this review we discuss the significance of novel findings related to cell signaling events modulated by APP and PSs for AD development.
Topics: Amyloid beta-Protein Precursor; Animals; Humans; Mitogen-Activated Protein Kinases; Models, Biological; Presenilins; Signal Transduction
PubMed: 17596704
DOI: 10.1159/000101834 -
Neuron Apr 2003Gamma-Secretase cleaves the Amyloid Precursor Protein (APP) in its transmembrane domain, releasing the amyloid peptide Abeta. Abeta is the main constituent of the... (Review)
Review
Gamma-Secretase cleaves the Amyloid Precursor Protein (APP) in its transmembrane domain, releasing the amyloid peptide Abeta. Abeta is the main constituent of the amyloid plaques in the brains of patients suffering from Alzheimer's disease. Several other type I integral membrane proteins are also cleaved by this protease. Recent work indicates that gamma-Secretase is a multiprotein complex consisting of Presenilin, Nicastrin, Aph-1, and Pen-2 and that all four proteins are necessary for full proteolytic activity. Since several paralogs and alternatively spliced variants of at least Presenilin and Aph-1 have been identified as well, it is anticipated that gamma-Secretase is not a homogeneous activity. Gamma-Secretase is an interesting but complex drug target that challenges classical thinking about proteolytic processing and intracellular signaling.
Topics: Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Endopeptidases; Humans; Membrane Glycoproteins; Membrane Proteins; Peptide Hydrolases; Presenilin-1; Presenilin-2; Protein Binding
PubMed: 12691659
DOI: 10.1016/s0896-6273(03)00205-8 -
Acta Neuropathologica Communications Sep 2021Mutations in the presenilin (PS/PSEN) genes encoding the catalytic components of γ-secretase accelerate amyloid-β (Aβ) and tau pathologies in familial Alzheimer's...
Mutations in the presenilin (PS/PSEN) genes encoding the catalytic components of γ-secretase accelerate amyloid-β (Aβ) and tau pathologies in familial Alzheimer's disease (AD). Although the mechanisms by which these mutations affect Aβ are well defined, the precise role PS/γ-secretase on tau pathology in neurodegeneration independently of Aβ is largely unclear. Here we report that neuronal PS deficiency in conditional knockout (cKO) mice results in age-dependent brain atrophy, inflammatory responses and accumulation of pathological tau in neurons and glial cells. Interestingly, genetic inactivation of presenilin 1 (PS1) or both PS genes in mutant human Tau transgenic mice exacerbates memory deficits by accelerating phosphorylation and aggregation of tau in excitatory neurons of vulnerable AD brain regions (e.g., hippocampus, cortex and amygdala). Remarkably, neurofilament (NF) light chain (NF-L) and phosphorylated NF are abnormally accumulated in the brain of Tau mice lacking PS. Synchrotron infrared microspectroscopy revealed aggregated and oligomeric β-sheet structures in amyloid plaque-free PS-deficient Tau mice. Hippocampal-dependent memory deficits are associated with synaptic tau accumulation and reduction of pre- and post-synaptic proteins in Tau mice. Thus, partial loss of PS/γ-secretase in neurons results in temporal- and spatial-dependent tau aggregation associated with memory deficits and neurodegeneration. Our findings show that tau phosphorylation and aggregation are key pathological processes that may underlie neurodegeneration caused by familial AD-linked PSEN mutations.
Topics: Alzheimer Disease; Animals; Brain; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neurons; Phosphorylation; Presenilins; Protein Aggregation, Pathological; tau Proteins
PubMed: 34593029
DOI: 10.1186/s40478-021-01259-7