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Yi Chuan = Hereditas Nov 2011In Drosophila, presenilin is an aspartyl protease that plays important roles in the development and calcium homeostasis. It has been expressed all through the fly... (Review)
Review
In Drosophila, presenilin is an aspartyl protease that plays important roles in the development and calcium homeostasis. It has been expressed all through the fly developmental process. The loss of Drosophila presenilin (DPS) function causes significantly decreased Notch signaling and neuron apoptosis and increased cytoplasm calcium. This subsequently led to impaired long term memory and cognitive deficits. Therefore, study of DPS is one of the most popular models for Alzheimer's disease research, and has provided important insights into the pathological mechanisms of AD. This review is to summarize the AD related function of DPS gene.
Topics: Amino Acid Sequence; Animals; Apoptosis; Calcium; Drosophila Proteins; Drosophila melanogaster; Humans; Molecular Sequence Data; Neurons; Presenilins; Sequence Alignment; Signal Transduction
PubMed: 22120070
DOI: 10.3724/sp.j.1005.2011.01164 -
Journal of Alzheimer's Disease : JAD 2018PRESENILIN 1 (PSEN1) and PRESENILIN 2 (PSEN2) genes are loci for mutations causing familial Alzheimer's disease (fAD). However, the function of these genes and how they... (Review)
Review
PRESENILIN 1 (PSEN1) and PRESENILIN 2 (PSEN2) genes are loci for mutations causing familial Alzheimer's disease (fAD). However, the function of these genes and how they contribute to fAD pathogenesis has not been fully determined. This review provides a summary of the overlapping and independent functions of the PRESENILINS with a focus on the lesser studied PSEN2. As a core component of the γ-secretase complex, the PSEN2 protein is involved in many γ-secretase-related physiological activities, including innate immunity, Notch signaling, autophagy, and mitochondrial function. These physiological activities have all been associated with AD progression, indicating that PSEN2 plays a particular role in AD pathogenesis.
Topics: Alzheimer Disease; Animals; Disease Progression; Humans; Mutation; Presenilin-1; Presenilin-2; Signal Transduction
PubMed: 30412492
DOI: 10.3233/JAD-180656 -
Proceedings of the National Academy of... Jan 2017
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Humans; Mutation; Presenilin-1; Presenilin-2
PubMed: 28082723
DOI: 10.1073/pnas.1619574114 -
Neuro-degenerative Diseases 2014The presenilin(PS) genes harbor approximately 90% of the identified mutations linked to familial forms of Alzheimer's disease, and the presenilin (PS) proteins are... (Review)
Review
The presenilin(PS) genes harbor approximately 90% of the identified mutations linked to familial forms of Alzheimer's disease, and the presenilin (PS) proteins are essential components of the γ-secretase complex involved in the proteolytic cleavage of type I receptors, such as Notch and the amyloid precursor protein. Genetic analysis employing cell type-specific conditional knockout technology highlighted the importance of PS in the adult brain, including learning and memory, synaptic function and age-dependent neuronal survival. In the central synapse, PS regulates neurotransmitter release, short- and long-term synaptic plasticity and calcium homeostasis. However, the molecular mechanisms by which PS maintains these essential functions are less clear. Although many γ-secretase substrates have been identified, their physiological relevance is often unclear. The findings that nicastrin and PS conditional knockout mice exhibit similar deficits in memory and age-dependent neurodegeneration are consistent with the notion that γ-secretase-dependent activities of PS are required for the maintenance of memory and neuronal survival, though the γ-secretase physiological substrates, Notch receptors, are not targets of PS in the adult brain. Thus, despite of the intense interest in PS since its identification in 1995, more work is needed to define the molecular and cellular mechanisms by which PS controls brain functions and the dysfunction conferred by disease-causing mutations.
Topics: Alzheimer Disease; Animals; Humans; Presenilins
PubMed: 24107444
DOI: 10.1159/000354971 -
Proceedings of the National Academy of... Jul 2017
Topics: Alzheimer Disease; Presenilin-1; Presenilin-2
PubMed: 28645897
DOI: 10.1073/pnas.1707809114 -
Proceedings of the National Academy of... Jan 2007Dominantly inherited mutations in the genes encoding presenilins (PS) and the amyloid precursor protein (APP) are the major causes of familial Alzheimer's disease (AD).... (Review)
Review
Dominantly inherited mutations in the genes encoding presenilins (PS) and the amyloid precursor protein (APP) are the major causes of familial Alzheimer's disease (AD). The prevailing view of AD pathogenesis posits that accumulation of beta-amyloid (Abeta) peptides, particularly Abeta42, is the central event triggering neurodegeneration. Emerging evidence, however, suggests that loss of essential functions of PS could better explain dementia and neurodegeneration in AD. First, conditional inactivation of PS in the adult mouse brain causes progressive memory loss and neurodegeneration resembling AD, whereas mouse models based on overproduction of Abeta have failed to produce neurodegeneration. Second, whereas pathogenic PS mutations enhance Abeta42 production, they typically reduce Abeta40 generation and impair other PS-dependent activities. Third, gamma-secretase inhibitors can enhance the production of Abeta42 while blocking other gamma-secretase activities, thus mimicking the effects of PS mutations. Finally, PS mutations have been identified in frontotemporal dementia, which lacks amyloid pathology. Based on these and other observations, we propose that partial loss of PS function may underlie memory impairment and neurodegeneration in the pathogenesis of AD. We also speculate that Abeta42 may act primarily to antagonize PS-dependent functions, possibly by operating as an active site-directed inhibitor of gamma-secretase.
Topics: Alzheimer Disease; Amino Acid Sequence; Amyloid Precursor Protein Secretases; Amyloid beta-Protein Precursor; Animals; Brain; Disease Models, Animal; Humans; Mice; Mice, Knockout; Models, Neurological; Molecular Sequence Data; Mutation; Nerve Degeneration; Presenilins
PubMed: 17197420
DOI: 10.1073/pnas.0608332104 -
Human Molecular Genetics 1996A positional cloning approach has led to the identification of two closely related genes, the presenilins (PS), for autosomal dominant presenile Alzheimer disease (AD):... (Review)
Review
A positional cloning approach has led to the identification of two closely related genes, the presenilins (PS), for autosomal dominant presenile Alzheimer disease (AD): PS-1 at 14q24.3 and PS-2 at 1q31-q42. The PS-1 gene was identified by direct cDNA selection of yeast artificial chromosomes containing the candidate chromosomal region. Subsequently, the PS-2 gene was identified due to its high sequence homology with PS-1 and its location within the candidate region defined by linkage studies. To date, 30 different missense mutations and one in-frame splice site mutation were described in PS-1, while only two missense mutations were detected in PS-2, suggesting that PS-1 mutations are more frequently involved in familial presenile AD. The PS transcripts encode novel proteins that resemble integral transmembrane proteins of roughly 450 amino acids and at least seven transmembrane domains. The genomic organization of the PS genes is very similar showing that full length PS-1 and PS-2 are encoded by 10 exons. However, different alternative splicing patterns have been observed for PS-1 and PS-2 indicating that the corresponding proteins (ps-1 and ps-2) may have similar but not identical biological functions.
Topics: Alzheimer Disease; Amino Acid Sequence; Animals; Cloning, Molecular; Gene Expression; Humans; Membrane Proteins; Molecular Sequence Data; Mutation; Presenilin-1; Presenilin-2; Sequence Homology, Amino Acid
PubMed: 8875251
DOI: 10.1093/hmg/5.supplement_1.1449 -
Journal of Alzheimer's Disease : JAD 2016Studies of presenilin (PSEN) gene mutations producing early onset Alzheimer's disease (AD) have helped elucidate the pathogenic mechanisms of dementia and guided... (Review)
Review
Studies of presenilin (PSEN) gene mutations producing early onset Alzheimer's disease (AD) have helped elucidate the pathogenic mechanisms of dementia and guided clinical trials of potential therapeutic interventions. Although familial and sporadic forms of AD share features, it is unclear if the two are precisely equivalent. In addition, PSEN mutations do not all produce a single phenotype, but exhibit substantial variability in clinical manifestations, which are related to the position and chemical nature of their amino acid substitutions as well as ratios of critical molecules such as Aβ40 and Aβ42. These differences complicate the interpretation of critical clinical trial results and their desired extrapolation to sporadic AD treatment. In this perspective, we examine differences between familial AD and sporadic AD as well as attributes shared by these uniquely arising disturbances in brain biochemical homeostasis that culminate in dementia.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Brain; Humans; Mutation; Presenilins
PubMed: 26757189
DOI: 10.3233/JAD-150757 -
Protein Science : a Publication of the... Jul 2016Presenilin is an integral membrane aspartate protease that regulates cellular processes by cleaving proteins within the cell membrane. The recent crystal structure of...
Presenilin is an integral membrane aspartate protease that regulates cellular processes by cleaving proteins within the cell membrane. The recent crystal structure of presenilin reveals a conspicuous pore in a bundle of nine α-helices, which was originally thought to adopt a novel protein fold. However, here I show that the presenilin fold is a variant of the ClC chloride channel/transporter fold. This observation may have important implications for presenilin's postulated biological role as a calcium leak channel.
Topics: Animals; Chloride Channels; Crystallography, X-Ray; Models, Molecular; Presenilins; Protein Folding; Protein Structure, Secondary; Structure-Activity Relationship
PubMed: 26971579
DOI: 10.1002/pro.2919 -
Journal of Alzheimer's Disease : JAD Nov 2006Molecular genetic studies of familial Alzheimer's disease by 1995 had clearly implicated three proteins as critical to Alzheimer's disease (AD), the amyloid-beta protein... (Review)
Review
Molecular genetic studies of familial Alzheimer's disease by 1995 had clearly implicated three proteins as critical to Alzheimer's disease (AD), the amyloid-beta protein precursor (AbetaPP) and the two homologous presenilins, PS-1 and PS-2. To account for the roles of these proteins in AD, we had proposed that as an early and critical step in the mechanisms that lead to AD, the PS on the surface of a brain cell engages in a specific receptor-ligand intercellular interaction with AbetaPP on the surface of a neighboring cell. This cell-cell interaction is required to trigger off a cascade of processes that lead to the production of amyloid-beta (Abeta) from AbetaPP, leading to AD. At about this time, however, many established AD researchers had obtained data that appeared to disagree with our proposed mechanism. Their immediate objections to our proposal were based on their conclusions that 1) The PS proteins were exclusively intracellular, and were not expressed at the cell surface, and 2) The topography of the PS proteins in intracellular membranes exhibits either 6 or 8-TM spanning domains, not 7. Here we discuss the evidence for the 6-TM, 7-TM, 8-TM and other models of PS topography and offer possibilities for the differences in interpretation of the various sets of data. We review the experimental demonstration of the cell-surface expression and the 7-TM structure of PS, the functional consequences of this structure, and the findings that PS-1 and PS-2 are members of the superfamily of 7-TM heterotrimeric G-protein coupled receptors (GPCRs).
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Antibodies, Monoclonal; Brain; Fluorescent Antibody Technique; Humans; Presenilin-1; Presenilin-2; Presenilins; Receptors, G-Protein-Coupled
PubMed: 17119293
DOI: 10.3233/jad-2006-102-312