Figure - available via license: Creative Commons Attribution 2.0 Generic
Content may be subject to copyright.
γ-secretase complex and the formation of the catalytic pore of PS1. PS1 transmembrane domains (TMDs) are shown as columns with numbers. Without the assistance of other subunits, PS1 forms a relatively open pore structure within the membrane. Upon the binding of subunits, the PALP motif moves to the proximity of the catalytic center, and the catalytic structure is activated by the structural changes in TMDs of PS1.
Source publication
Presenilins (PSs) are the catalytic core of gamma-secretase complex. However, the mechanism of FAD-associated PS mutations in AD pathogenesis still remains elusive. Here we review the general biology and mechanism of gamma-secretase and focus on the catalytic components -- presenilins and their biological functions and contributions to the AD patho...
Context in source publication
Context 1
... constitutive autoendoproteolysis of PS removes the inhibitory allosteric effect of the large hydrophobic loop from the catalytic chamber structure in PS [64,65]. With direct interaction be- tween γ-secretase components [85,86], Nct/Aph-1 sub- units and Pen-2 tighten the relative loose PS TM6/ TM7/TM9 intramembrane cavity and rearrange the PALP motif of TM9 to the proximity of the catalytic center, thus activate the γ-secretase complex [87] (Figure 3). Recently, Li et al. reported the crystal structure of a presenilin/SPP homologue (PSH) from the archaeon Methanoculleus marisnigri JR1 and predicted the structure of presenilin based on the conserved sequence between the two homo- logues [88]. ...Citations
... This high molecular weight complex also requires the presence of nicastrin, anterior pharynx-defective 1 (APH-1), and PEN-2 for its enzymatic activity. 28 PS1 and PS2 are homologous with 67% identical sequences. They are both ubiquitously expressed in human and mouse tissue, while PS1 mRNA levels are significantly higher in developing brains. ...
Mutations in the Contactin-associated protein-like 2 (CNTNAP2) gene are associated with autism spectrum disorder (ASD), and ectodomain shedding of the CNTNAP2 protein plays a role in its function. However, key enzymes involved in the C-terminal cleavage of CNTNAP2 remain largely unknown, and the effect of ASD-associated mutations on this process and its role in ASD pathogenesis remain elusive. In this report we showed that CNTNAP2 undergoes sequential cleavages by furin, ADAM10/17-dependent α-secretase and presenilin-dependent γ-secretase. We identified that the cleavage sites of ADAM10 and ADAM17 in CNTNAP2 locate at its C-terminal residue I79 and L96, and the main α-cleavage product C79 by ADAM10 is required for the subsequent γ-secretase cleavage to generate CNTNAP2 intracellular domain (CICD). ASD-associated CNTNAP2 mutations impair the α-cleavage to generate C79, and the inhibition leads to ASD-like repetitive and social behavior abnormalities in the Cntnap2-I1254T knock-in mice. Finally, exogenous expression of C79 improves autism-like phenotypes in the Cntnap2-I1254T knock-in and Cntnap2-/- knockout mice. This data demonstrates that the α-secretase is essential for CNTNAP2 processing and its function. Our study indicates that inhibition of the cleavage by pathogenic mutations underlies ASD pathogenesis, and upregulation of its C-terminal fragments could have therapeutical potentials for ASD treatment.
... Number and function of ryanodine receptors (RyR) are also increased in mouse models containing mutations PS1 M146V and PS2 N141I (Supnet and Bezprozvanny, 2011). At the same time, there is evidence suggesting that transmembrane domains 7 and 9 of PS1 have been implicated in pore-forming of an ionic conduction as Ca 2+ − leak channel (Zhang et al., 2013). However, the PS1-M146V, PS2-N141I, and some others mutations disrupt or abolish this leak, resulting in ER Ca 2+ overload (Nelson et al., 2007). ...
This review uncovers the intricate relationship between presenilins, calcium, and mitochondria in the context of Alzheimer’s disease (AD), with a particular focus on the involvement of presenilin mutations in mitochondrial dysfunction. So far, it is unclear whether the impairment of mitochondrial function arises primarily from damage inflicted by β-amyloid upon mitochondria or from the disruption of calcium homeostasis due to presenilins dysfunctions. The roles of presenilins in mitophagy, autophagy, mitochondrial dynamics, and many other functions, non-γ-secretase related, also require close attention in future research. Resolution of contradictions in understanding of presenilins cellular functions are needed for new effective therapeutic strategies for AD.
... Subsequently, γ-secretase cleaves C99 to release Aβ and CTFγ. γ-secretase is a presenilins 1 (PS1)-containing macromolecular complex [12][13][14][15][16] and this high molecular weight complex also requires nicastrin, anterior pharynx-defective 1, and PEN-2 for its enzymatic activity 17,18 (Fig. 1). ...
Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer's disease (AD), and its accumulation has been considered as the molecular driver of Alzheimer's pathogenesis and progression. Aβ has been the prime target for the development of AD therapy. However, the repeated failures of Aβ-targeted clinical trials have cast considerable doubt on the amyloid cascade hypothesis and whether the development of Alzheimer's drug has followed the correct course. However, the recent successes of Aβ targeted trials have assuaged those doubts. In this review, we discussed the evolution of the amyloid cascade hypothesis over the last 30 years and summarized its application in Alzheimer's diagnosis and modification. In particular, we extensively discussed the pitfalls, promises and important unanswered questions regarding the current anti-Aβ therapy, as well as strategies for further study and development of more feasible Aβ-targeted approaches in the optimization of AD prevention and treatment.
... Aβ generation has traditionally been thought to involve continuous cleavage of β-and γ-secretase [44,45]. Accordingly, mutations in PSEN1, PSEN2, and APP, identified in FAD, were reported to increase Aβ production by regulating the catalytic activity and/or aberrant expression of proteins [46]. The proteolytic events resulting in Aβ production are well characterized [47], but do not explain the mechanism in pedigrees without PSEN1/PSEN2 or APP mutations. ...
Background
The identification of pathogenic mutations in Alzheimer’s disease (AD) causal genes led to a better understanding of the pathobiology of AD. Familial Alzheimer’s disease (FAD) is known to be associated with mutations in the APP, PSEN1, and PSEN2 genes involved in Aβ production; however, these genetic defects occur in only about 10–20% of FAD cases, and more genes and new mechanism causing FAD remain largely obscure.
Methods
We performed exome sequencing on family members with a FAD pedigree and identified gene variant ZDHHC21 p.T209S. A ZDHHC21T209S/T209S knock-in mouse model was then generated using CRISPR/Cas9. The Morris water navigation task was then used to examine spatial learning and memory. The involvement of aberrant palmitoylation of FYN tyrosine kinase and APP in AD pathology was evaluated using biochemical methods and immunostaining. Aβ and tau pathophysiology was evaluated using ELISA, biochemical methods, and immunostaining. Field recordings of synaptic long-term potentiation were obtained to examine synaptic plasticity. The density of synapses and dendritic branches was quantified using electron microscopy and Golgi staining.
Results
We identified a variant (c.999A > T, p.T209S) of ZDHHC21 gene in a Han Chinese family. The proband presented marked cognitive impairment at 55 years of age (Mini-Mental State Examination score = 5, Clinical Dementia Rating = 3). Considerable Aβ retention was observed in the bilateral frontal, parietal, and lateral temporal cortices. The novel heterozygous missense mutation (p.T209S) was detected in all family members with AD and was not present in those unaffected, indicating cosegregation. ZDHHC21T209S/T209S mice exhibited cognitive impairment and synaptic dysfunction, suggesting the strong pathogenicity of the mutation. The ZDHHC21 p.T209S mutation significantly enhanced FYN palmitoylation, causing overactivation of NMDAR2B, inducing increased neuronal sensitivity to excitotoxicity leading to further synaptic dysfunction and neuronal loss. The palmitoylation of APP was also increased in ZDHHC21T209S/T209S mice, possibly contributing to Aβ production. Palmitoyltransferase inhibitors reversed synaptic function impairment.
Conclusions
ZDHHC21 p.T209S is a novel, candidate causal gene mutation in a Chinese FAD pedigree. Our discoveries strongly suggest that aberrant protein palmitoylation mediated by ZDHHC21 mutations is a new pathogenic mechanism of AD, warranting further investigations for the development of therapeutic interventions.
... Since their identification, PSs have also been found to be involved in biological functions independently of their γ-secretase activity, including cellular calcium (Ca 2+ ) homeostasis, mitochondrial metabolism, autophagy, and protein transport [5]. Notably, both PSs have been found enriched at mitochondria-associated membranes (MAMs) [6], suggesting their involvement in ER-mitochondria communication. ...
Mutations in presenilin 2 (PS2) have been causally linked to the development of inherited Alzheimer’s disease (AD). Besides its role as part of the γ-secretase complex, mammalian PS2 is also involved, as an individual protein, in a growing number of cell processes, which result altered in AD. To gain more insight into PS2 (dys)functions, we have generated a presenilin2 (psen2) knockout zebrafish line. We found that the absence of the protein does not markedly influence Notch signaling at early developmental stages, suggesting a Psen2 dispensable role in the γ-secretase-mediated Notch processing. Instead, loss of Psen2 induces an exaggerated locomotor response to stimulation in fish larvae, a reduced number of ER-mitochondria contacts in zebrafish neurons, and an increased basal autophagy. Moreover, the protein is involved in mitochondrial axonal transport, since its acute downregulation reduces in vivo organelle flux in zebrafish sensory neurons. Importantly, the expression of a human AD-linked mutant of the protein increases this vital process. Overall, our results confirm zebrafish as a good model organism for investigating PS2 functions in vivo, representing an alternative tool for the characterization of new AD-linked defective cell pathways and the testing of possible correcting drugs.
... . Mutations in each of the subunits and in the amyloid precursor protein cause the accumulation of amyloid-beta peptides, which contribute to the pathogenicity of AD due to their toxicity in brain neurons [3][4][5]. Two types of PSEN2 protein are produced by variable or intermittent overlap. An irregular PSEN2 overlap does not have Exon 5, which leads to the addition of five amino acids, SSMAG, into the protein, creating an inappropriate end codon in Exon6. ...
Background and Aims: One of the most important genes involved in Alzheimer's disease (AD) is the presenilin2 (PSEN2) gene, which is one of the main constituents of the gamma-secretase complex. Mutations in this gene promote the formation of amyloid plaques resulting in AD. The study aimed to evaluate the mutation variant in exon 6 of the PSEN2 gene in patients with Late-Onset Alzheimer's disease (LOAD). Due to the important role of the PSEN2 gene in the formation of beta-amyloid aggregates and the investigation involves an association between PSEN2 mutations and their pathogenicity in LOAD progression, we presented this exon as a more efficient alternative. Materials and Methods: The thirty patients with LOAD and 16 healthy subjects as a control group were involved in this experimental study. DNA was extracted from blood samples and purified. The desired gene fragment was propagated using polymerase chain reaction and the products were electrophoresed and the results were analyzed. Result: A novel mutation was found in PSEN2 IVS6 + 30 G → C at the intron region of exon 6 in 20 cases of patients suffering from LOAD and 12 subjects in control cohort. In this mutation a guanine base was substituted by cytosine base which this position was 30 nucleotides separated from coding region. Conclusions: The novel mutation was identified in both studied groups. These findings reveal no relationship between PSEN2 mutation and pathogenicity of LOAD disease. However, further studies are required to find the role of PSEN2 mutation in LOAD progression.
... To better understand the impact of subcellular localization on amyloidogenic processing (see Figure 4), one must keep in mind that γ-secretase is composed of four subunits, namely, Nicastrin, Aph1, Pen-2, and Presenilin 1/2 (PS1/2, encoded by the PSEN1 and PSEN2 genes, respectively) [102]. The catalytic core of γ-secretase is composed of either PS1 or PS2, which harbor two aspartate catalytic residues (e.g., Asp287 and Asp387 for PS1) [103,104]. The fact that mutations in PSs are the most common cause of FAD highlights their critical role in the pathology (for a review see [105]). ...
Most neurodegenerative diseases have the characteristics of protein folding disorders, i.e., they cause lesions to appear in vulnerable regions of the nervous system, corresponding to protein aggregates that progressively spread through the neuronal network as the symptoms progress. Alzheimer’s disease is one of these diseases. It is characterized by two types of lesions: neurofibrillary tangles (NFTs) composed of tau proteins and senile plaques, formed essentially of amyloid peptides (Aβ). A combination of factors ranging from genetic mutations to age-related changes in the cellular context converge in this disease to accelerate Aβ deposition. Over the last two decades, numerous studies have attempted to elucidate how structural determinants of its precursor (APP) modify Aβ production, and to understand the processes leading to the formation of different Aβ aggregates, e.g., fibrils and oligomers. The synthesis proposed in this review indicates that the same motifs can control APP function and Aβ production essentially by regulating membrane protein dimerization, and subsequently Aβ aggregation processes. The distinct properties of these motifs and the cellular context regulate the APP conformation to trigger the transition to the amyloid pathology. This concept is critical to better decipher the patterns switching APP protein conformation from physiological to pathological and improve our understanding of the mechanisms underpinning the formation of amyloid fibrils that devastate neuronal functions.
... As mentioned before, Psen1 is the catalytic subunit of the γ-secretase complex and also has secretase-independent functions, which are poorly characterised. 21 To determine if the observed effect on EGFR expression is mediated by a γ-secretase dependent or independent function, we stimulated control tumouroids with DAPT, a commercially available GSI. As a result of this inhibition and in agreement with our genetic approach, the expression of Egfr was clearly downregulated (figure 5F), suggesting that Psen1 modulates the expression of EGFR through a mechanism that is γ-secretase dependent rather than through, for example, scaffolding functions of Psen1. ...
Objective
Psen1 was previously characterised as a crucial factor in the pathogenesis of neurodegeneration in patients with Alzheimer’s disease. Little, if any, is known about its function in the gut. Here, we uncovered an unexpected functional role of Psen1 in gut epithelial cells during intestinal tumourigenesis.
Design
Human colorectal cancer (CRC) and control samples were investigated for PSEN1 and proteins of theγ-secretase complex. Tumour formation was analysed in the AOM-DSS and Apc min/+ mouse models using newly generated epithelial-specific Psen1 deficient mice. Psen1 deficient human CRC cells were studied in a xenograft tumour model. Tumour-derived organoids were analysed for growth and RNA-Seq was performed to identify Psen1-regulated pathways. Tumouroids were generated to study EGFR activation and evaluation of the influence of prostanoids.
Results
PSEN1 is expressed in the intestinal epithelium and its level is increased in human CRC. Psen1 -deficient mice developed only small tumours and human cancer cell lines deficient in Psen1 had a reduced tumourigenicity. Tumouroids derived from Psen1 -deficient Apc min/+ mice exhibited stunted growth and reduced cell proliferation. On a molecular level, PSEN1 potentiated tumour cell proliferation via enhanced EGFR signalling and COX-2 production. Exogenous administration of PGE 2 reversed the slow growth of PSEN1 deficient tumour cells via PGE 2 receptor 4 (EP4) receptor signalling.
Conclusions
Psen1 drives tumour development by increasing EGFR signalling via NOTCH1 processing, and by activating the COX-2-PGE 2 pathway. PSEN1 inhibition could be a useful strategy in treatment of CRC.
... The catalytic core of -secretase is composed by either PS1 276 or PS2 which harbor two aspartate catalytic residues (e.g. Asp287 and Asp387 for PS1) [110,111]. The fact that mutations 277 in PSs are the most common cause of FAD highlights their critical role in the pathology (for a review see [112]). ...
Most neurodegenerative diseases have the characteristics of proteinopathies, i.e. they cause lesions to appear in vulnerable regions of the nervous system, corresponding to protein aggregates that progressively spread through the neuronal network as the symptoms progress. Alzheimer's disease is one of these proteinopathies. It is characterized by two lesions, neurofibrillary tangles (NFTs) and senile plaques, formed essentially of amyloid peptides (Aβ). A combination of factors ranging from genetic mutations to age-related changes in the cellular context converge in this disease to accelerate Aβ deposition. Over the last two decades, numerous studies have attempted to elucidate how structural determinants of its precursor (APP) modify Aβ production, and to understand the processes leading to the formation of different Aβ aggregates; e.g. fibrils and oligomers. The synthesis proposed in this review indicates that the same motifs can control APP function and Aβ production essentially by regulating membrane dimerization, and subsequently Aβ aggregation processes. The distinct properties of these motifs and the cellular context regulate the APP conformation to trigger the transition to the amyloid pathology. This concept can be transposed to the study of other proteinopathies, providing a framework for improving our understanding of these mechanisms that devastate neuronal functions.
... Presenilins are elevated in Alzheimer's disease and increase the likelihood of its development [45,46]. It has been shown that the activity of presenilins can be divided into γ-secretase-dependent and γ-secretase-independent [47]. An example of the γ-secretase-dependent action of presenilins is the presence of cuts during the metabolism of the amyloid protein precursor [47]. ...
... It has been shown that the activity of presenilins can be divided into γ-secretase-dependent and γ-secretase-independent [47]. An example of the γ-secretase-dependent action of presenilins is the presence of cuts during the metabolism of the amyloid protein precursor [47]. Moreover, the γ-secretase-independent action of presenilins includes the stabilization of β-catenin in the Wnt signaling pathway, the regulation of calcium homeostasis, and their interaction with synaptic transmission [47]. ...
... An example of the γ-secretase-dependent action of presenilins is the presence of cuts during the metabolism of the amyloid protein precursor [47]. Moreover, the γ-secretase-independent action of presenilins includes the stabilization of β-catenin in the Wnt signaling pathway, the regulation of calcium homeostasis, and their interaction with synaptic transmission [47]. ...
In this study, the expression of the genes of the amyloid protein precursor, β-secretase, presenilin 1 and 2 by RT-PCR in the lymphocytes of newborns after perinatal asphyxia and perinatal asphyxia treated with hypothermia was analyzed at the age of 15–21 days. The relative quantification of Alzheimer’s-disease-related genes was first performed by comparing the peripheral lymphocytes of non-asphyxia control versus those with asphyxia or asphyxia with hypothermia. In the newborns who had perinatal asphyxia, the peripheral lymphocytes presented a decreased expression of the amyloid protein precursor and β-secretase genes. On the other hand, the expression of the presenilin 1 and 2 genes increased in the studied group. The expression of the studied genes in the asphyxia group treated with hypothermia had an identical pattern of changes that were not statistically significant to the asphyxia group. This suggests that the expression of the genes involved in the metabolism of the amyloid protein precursor in the peripheral lymphocytes may be a biomarker of progressive pathological processes in the brain after asphyxia that are not affected by hypothermia. These are the first data in the world showing the role of hypothermia in the gene changes associated with Alzheimer’s disease in the peripheral lymphocytes of newborns after asphyxia.
