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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 -
PloS One 2013Dietary copper is essential for multicellular organisms. Copper is redox active and required as a cofactor for enzymes such as the antioxidant Superoxide Dismutase 1...
Dietary copper is essential for multicellular organisms. Copper is redox active and required as a cofactor for enzymes such as the antioxidant Superoxide Dismutase 1 (SOD1). Copper dyshomeostasis has been implicated in Alzheimer's disease. Mutations in the presenilin genes encoding PS1 and PS2 are major causes of early-onset familial Alzheimer's disease. PS1 and PS2 are required for efficient copper uptake in mammalian systems. Here we demonstrate a conserved role for presenilin in dietary copper uptake in the fly Drosophila melanogaster. Ubiquitous RNA interference-mediated knockdown of the single Drosophila presenilin (PSN) gene is lethal. However, PSN knockdown in the midgut produces viable flies. These flies have reduced copper levels and are more tolerant to excess dietary copper. Expression of a copper-responsive EYFP construct was also lower in the midgut of these larvae, indicative of reduced dietary copper uptake. SOD activity was reduced by midgut PSN knockdown, and these flies were sensitive to the superoxide-inducing chemical paraquat. These data support presenilin being needed for dietary copper uptake in the gut and so impacting on SOD activity and tolerance to oxidative stress. These results are consistent with previous studies of mammalian presenilins, supporting a conserved role for these proteins in mediating copper uptake.
Topics: Animals; Biological Transport; Conserved Sequence; Copper; Diet; Drosophila melanogaster; Gene Knockdown Techniques; Insect Proteins; Oxidative Stress; Presenilins; RNA Interference; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 23667524
DOI: 10.1371/journal.pone.0062811 -
Biomolecules Nov 2020The increasing detection of infections of , the etiological agent of Chagas disease, in non-endemic regions beyond Latin America has risen to be a major public health...
The increasing detection of infections of , the etiological agent of Chagas disease, in non-endemic regions beyond Latin America has risen to be a major public health issue. With an impact in the millions of people, current treatments rely on antiquated drugs that produce severe side effects and are considered nearly ineffective for the chronic phase. The minimal progress in the development of new drugs highlights the need for advances in basic research on crucial biochemical pathways in to identify new targets. Here, we report on the presenilin-like transmembrane aspartyl enzyme, a protease of the aspartic class in a unique phylogenetic subgroup with separate from protozoans. Computational analyses suggest it contains nine transmembrane domains and an active site with the characteristic PALP motif of the A22 family. Multiple linear B-cell epitopes were identified by SPOT-synthesis analysis with Chagasic patient sera. Two were chosen to generate rabbit antisera, whose signal was primarily localized to the flagellar pocket, intracellular vesicles, and endoplasmic reticulum in parasites by whole-cell immunofluorescence. The results suggest that the parasitic presenilin-like enzyme could have a role in the secretory pathway and serve as a target for the generation of new therapeutics specific to the .
Topics: Animals; Aspartic Acid Proteases; Cell Membrane; Humans; Phylogeny; Pregnancy Proteins; Presenilins; Protozoan Proteins; Rabbits; Sequence Analysis, Protein; Trypanosoma cruzi
PubMed: 33212923
DOI: 10.3390/biom10111564 -
Neurochemical Research 2007The biogenesis and accumulation of the beta amyloid protein (Abeta) is a key event in the cascade of oxidative and inflammatory processes that characterises Alzheimer's... (Review)
Review
The biogenesis and accumulation of the beta amyloid protein (Abeta) is a key event in the cascade of oxidative and inflammatory processes that characterises Alzheimer's disease. The presenilins and its interacting proteins play a pivotal role in the generation of Abeta from the amyloid precursor protein (APP). In particular, three proteins (nicastrin, aph-1 and pen-2) interact with presenilins to form a large multi-subunit enzymatic complex (gamma-secretase) that cleaves APP to generate Abeta. Reconstitution studies in yeast and insect cells have provided strong evidence that these four proteins are the major components of the gamma-secretase enzyme. Current research is directed at elucidating the roles that each of these protein play in the function of this enzyme. In addition, a number of presenilin interacting proteins that are not components of gamma-secretase play important roles in modulating Abeta production. This review will discuss the components of the gamma-secretase complex and the role of presenilin interacting proteins on gamma-secretase activity.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Animals; Aspartic Acid Endopeptidases; Humans; Membrane Glycoproteins; Membrane Proteins; Nucleocytoplasmic Transport Proteins; Presenilins; Protein Binding; Substrate Specificity
PubMed: 16944319
DOI: 10.1007/s11064-006-9131-x -
Cell Jan 2011The Alzheimer's disease-linked gene presenilin is required for intramembrane proteolysis of amyloid-β precursor protein, contributing to the pathogenesis of...
The Alzheimer's disease-linked gene presenilin is required for intramembrane proteolysis of amyloid-β precursor protein, contributing to the pathogenesis of neurodegeneration that is characterized by loss of neuronal connections, but the role of Presenilin in establishing neuronal connections is less clear. Through a forward genetic screen in mice for recessive genes affecting motor neurons, we identified the Columbus allele, which disrupts motor axon projections from the spinal cord. We mapped this mutation to the Presenilin-1 gene. Motor neurons and commissural interneurons in Columbus mutants lacking Presenilin-1 acquire an inappropriate attraction to Netrin produced by the floor plate because of an accumulation of DCC receptor fragments within the membrane that are insensitive to Slit/Robo silencing. Our findings reveal that Presenilin-dependent DCC receptor processing coordinates the interplay between Netrin/DCC and Slit/Robo signaling. Thus, Presenilin is a key neural circuit builder that gates the spatiotemporal pattern of guidance signaling, thereby ensuring neural projections occur with high fidelity.
Topics: Animals; Axons; Chick Embryo; Glycoproteins; Mice; Mice, Transgenic; Mutation; Nerve Growth Factors; Nerve Tissue Proteins; Netrin-1; Neurodegenerative Diseases; Neurogenesis; Neurons; Presenilins; Receptors, Cell Surface; Receptors, Immunologic; Signal Transduction; Tumor Suppressor Proteins; Roundabout Proteins
PubMed: 21215373
DOI: 10.1016/j.cell.2010.11.053 -
EMBO Reports Feb 2007More than 100 missense mutations in presenilin 1 and 2 are associated with early-onset dominant Alzheimer disease. These proteins span the membrane several times and are... (Review)
Review
More than 100 missense mutations in presenilin 1 and 2 are associated with early-onset dominant Alzheimer disease. These proteins span the membrane several times and are ostensibly the catalytic component of the gamma-secretase complex, which is responsible for producing the amyloid beta-peptide (Abeta) that deposits in the Alzheimer brain. A common outcome of Alzheimer-associated presenilin mutations is an increase in the ratio of the more aggregation-prone 42-residue form of Abeta to the 40-residue variant, which is often referred to as a presenilin 'gain of function'. An apparent paradox is that most of these mutant presenilins have reduced proteolytic efficiency, which forms part of the counter argument that presenilin 'loss of function' can cause the neuronal dysfunction and death that lead to the disease. In this review, a unifying hypothesis is presented that puts forward a biochemical mechanism by which slower less-efficient forms of the protease can result in a greater proportion of 42-residue Abeta.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Humans; Models, Biological; Mutation; Peptide Fragments; Presenilins
PubMed: 17268504
DOI: 10.1038/sj.embor.7400896 -
Proceedings of the National Academy of... Jan 2019Presenilin is the catalytic subunit of γ-secretase, a four-component intramembrane protease responsible for the generation of β-amyloid (Aβ) peptides. Over 200...
Presenilin is the catalytic subunit of γ-secretase, a four-component intramembrane protease responsible for the generation of β-amyloid (Aβ) peptides. Over 200 Alzheimer's disease-related mutations have been identified in presenilin 1 (PS1) and PS2. Here, we report that Bax-inhibitor 1 (BI1), an evolutionarily conserved transmembrane protein, stably associates with PS1. BI1 specifically interacts with PS1 in isolation, but not with PS1 in the context of an assembled γ-secretase. The PS1-BI1 complex exhibits no apparent proteolytic activity, as judged by the inability to produce Aβ40 and Aβ42 from the substrate APP-C99. At an equimolar concentration, BI1 has no impact on the proteolytic activity of γ-secretase; at a 200-fold molar excess, BI1 reduces γ-secretase activity nearly by half. Our biochemical study identified BI1 as a PS1-interacting protein, suggesting additional functions of PS1 beyond its involvement in γ-secretase.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Apoptosis Regulatory Proteins; Blotting, Western; HEK293 Cells; Humans; In Vitro Techniques; Membrane Proteins; Microscopy, Confocal; Presenilin-1; Presenilins
PubMed: 30559186
DOI: 10.1073/pnas.1810870116 -
Neuro-degenerative Diseases 2006The genome of the nematode Caenorhabditis elegans contains homologs of several genes associated with familial Alzheimer's disease in humans. apl-1 encodes a...
The genome of the nematode Caenorhabditis elegans contains homologs of several genes associated with familial Alzheimer's disease in humans. apl-1 encodes a transmembrane protein belonging to the amyloid precursor protein family, sel-12 and hop-1 are the two somatically expressed presenilin genes that resemble PS1 and PS2 on both a structural and a functional level. Mutations in the sel-12-encoded presenilin gene cause defective Notch/lin-12 signaling and result in reduced egg-laying, caused by cell specification and cell attachment defects. spr-1, spr-3, spr-4 and spr-5 were identified as the suppressors of the egg-laying defect of presenilin/sel-12 loss of function mutants in genetic suppressor screens. The corresponding proteins are C. elegans homologs of human REST, CoREST and LSD1, respectively. REST/NSRF (Re1 silencing transcription factor/neural-restrictive silencing factor) is a transcriptional repressor that blocks the expression of neuronal genes in non-neuronal tissues in vertebrates. CoREST is a conserved histone deacetylase and demethylase-containing co-repressor complex possessing a potential chromatin-modifying activity. It is recruited to the promoter via REST-mediated DNA binding. LSD1 is a flavin-dependent demethylase of histone H3. Mutations in spr-1, spr-3, spr-4 and spr-5 genes suppress the egg-laying phenotype of sel-12 loss of function mutants by derepressing the expression of the second C. elegans presenilin gene, hop-1.
Topics: Alzheimer Disease; Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Humans; Presenilins; Receptors, Notch
PubMed: 17047361
DOI: 10.1159/000095260 -
Journal of Cell Science Jul 2021Presenilins (PSENs) are widely expressed across eukaryotes. Two PSENs are expressed in humans, where they play a crucial role in Alzheimer's disease (AD). Each PSEN can...
Presenilins (PSENs) are widely expressed across eukaryotes. Two PSENs are expressed in humans, where they play a crucial role in Alzheimer's disease (AD). Each PSEN can be part of the γ-secretase complex, which has multiple substrates, including Notch and amyloid-β precursor protein (AβPP) - the source of amyloid-β (Aβ) peptides that compose the senile plaques during AD. PSENs also interact with various proteins independently of their γ-secretase activity. They can then be involved in numerous cellular functions, which makes their role in a given cell and/or organism complex to decipher. We have established the Paracentrotus lividus sea urchin embryo as a new model to study the role of PSEN. In the sea urchin embryo, the PSEN gene is present in unduplicated form and encodes a protein highly similar to human PSENs. Our results suggest that PSEN expression must be precisely tuned to control the course of the first mitotic cycles and the associated intracellular Ca2+ transients, the execution of gastrulation and, probably in association with ciliated cells, the establishment of the pluteus. We suggest that it would be relevant to study the role of PSEN within the gene regulatory network deciphered in the sea urchin.
Topics: Animals; Presenilin-1; Presenilins; Sea Urchins
PubMed: 34313316
DOI: 10.1242/jcs.258382 -
Molecular Neurodegeneration Dec 2020Mutations in the PSEN1 and PSEN2 genes are the major cause of familial Alzheimer's disease. Previous studies demonstrated that Presenilin (PS), the catalytic subunit of...
BACKGROUND
Mutations in the PSEN1 and PSEN2 genes are the major cause of familial Alzheimer's disease. Previous studies demonstrated that Presenilin (PS), the catalytic subunit of γ-secretase, is required for survival of excitatory neurons in the cerebral cortex during aging. However, the role of PS in inhibitory interneurons had not been explored.
METHODS
To determine PS function in GABAergic neurons, we generated inhibitory neuron-specific PS conditional double knockout (IN-PS cDKO) mice, in which PS is selectively inactivated by Cre recombinase expressed under the control of the endogenous GAD2 promoter. We then performed behavioral, biochemical, and histological analyses to evaluate the consequences of selective PS inactivation in inhibitory neurons.
RESULTS
IN-PS cDKO mice exhibit earlier mortality and lower body weight despite normal food intake and basal activity. Western analysis of protein lysates from various brain sub-regions of IN-PS cDKO mice showed significant reduction of PS1 levels and dramatic accumulation of γ-secretase substrates. Interestingly, IN-PS cDKO mice develop age-dependent loss of GABAergic neurons, as shown by normal number of GAD67-immunoreactive interneurons in the cerebral cortex at 2-3 months of age but reduced number of cortical interneurons at 9 months. Moreover, age-dependent reduction of Parvalbumin- and Somatostatin-immunoreactive interneurons is more pronounced in the neocortex and hippocampus of IN-PS cDKO mice. Consistent with these findings, the number of apoptotic cells is elevated in the cerebral cortex of IN-PS cDKO mice, and the enhanced apoptosis is due to dramatic increases of apoptotic interneurons, whereas the number of apoptotic excitatory neurons is unaffected. Furthermore, progressive loss of interneurons in the cerebral cortex of IN-PS cDKO mice is accompanied with astrogliosis and microgliosis.
CONCLUSION
Our results together support a cell-autonomous role of PS in the survival of cortical interneurons during aging. Together with earlier studies, these findings demonstrate a universal, essential requirement of PS in the survival of both excitatory and inhibitory neurons during aging.
Topics: Age Factors; Aging; Animals; Brain; Cerebral Cortex; Hippocampus; Interneurons; Mice; Presenilin-1; Presenilins
PubMed: 33302995
DOI: 10.1186/s13024-020-00419-y