Genetics, Functions, and Clinical Impact of Presenilin-1 (PSEN1) Gene

Bagaria, Jaya; Bagyinszky, Eva; An, Seong Soo A.

doi:10.3390/ijms231810970

Cited by 39 publications

(39 citation statements)

References 303 publications

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“…In this way, it would be the loss of mechanical homeostasis and the shockwave-like spread of it from the initial foci(s) that would be why AD spreads across the brain. This idea is supported by the existence of AD-causing presenilin mutations that counter-intuitively limit cleavage of APP and hence reduce APP processing (Bagaria et al, 2022; Sun et al, 2017). However, these mutations still give rise to AD, fitting with the idea that this is due to defective force feedback signalling, with the result being that they also accelerate mechanical dyshomeostasis.…”

Section: Discussionmentioning

confidence: 99%

The structure of an Amyloid Precursor Protein/talin complex indicates a mechanical basis of Alzheimer's Disease.

Ellis,

Ward,

Rice

et al. 2024

Preprint

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Misprocessing of Amyloid Precursor Protein (APP) is one of the major causes of Alzheimer's disease. APP is a transmembrane protein comprising a large extracellular region, a single transmembrane helix and a short cytoplasmic tail containing an NPxY motif (normally referred to as the YENPTY motif). Talin is a synaptic scaffold protein that connects the cytoskeletal machinery to the plasma membrane via binding to one of two highly conserved NPxY motifs in the cytoplasmic tail of integrin transmembrane receptors. Here we report the crystal structure of an APP/talin complex identifying a new way to couple the cytoskeletal machinery to synaptic sites via APP. Structural modelling reveals that APP forms an extracellular meshwork that mechanically couples the cytoskeletal meshworks of both the pre-, and post-synaptic compartments. In this context, we propose APP processing as a mechanical signalling pathway with similarities to Notch signalling, whereby the cleavage sites in APP represent mechanical sensors, with varying accessibility to cleavage by secretases. During synaptogenesis in healthy neurons, the APP/talin linkage would provide an exquisite mechanical coupling between synapses, with tightly controlled APP processing providing instructions to maintain this synchrony. Furthermore, APP directly coupling to the binary switches in talin indicates a role for APP in mechanical memory storage as postulated by the MeshCODE theory. The implication that APP is a regulator of mechanical signalling leads to a new hypothesis for Alzheimer's disease, where mis-regulation of APP dynamics results in loss of mechanical integrity of the synapse, corruption and loss of mechanical binary data, and excessive generation of the toxic plaque-forming Aβ42 peptide. In support of this model, we show that talin1 depletion has a dramatic effect on APP processing in cells. Much needs to be done to experimentally validate this idea, but we present here a novel theory of Alzheimer's Disease with a role for APP in the mechanically coded binary information storage in the synapse, which identifies a potential novel therapeutic strategy for treating Alzheimer's Disease.

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Section: Discussionmentioning

confidence: 99%

The structure of an Amyloid Precursor Protein/talin complex indicates a mechanical basis of Alzheimer's Disease.

Ellis,

Ward,

Rice

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…Presenolin can regulate APP processing through γ-secretase. Current studies have shown that PSEN1 is mainly associated with Alzheimer’s disease, amyloidosis, cancer-related genes, cardiomyopathy, disease variation, and cognitive disorders [ 45 , 46 ]. PSEN1 is a well-known gene associated with MCI and AD [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Exploration and Clinical Verification of the Blood Co-Expression Genes of Type 2 Diabetes Mellitus and Mild Cognitive Dysfunction in the Elderly

et al. 2023

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With the development of society, the incidence of dementia and type 2 diabetes (T2DM) in the elderly has been increasing. Although the correlation between T2DM and mild cognitive impairment (MCI) has been confirmed in the previous literature, the interaction mechanism remains to be clarified. To explore the co-pathogenic genes in the blood of MCI and T2DM patients, clarify the correlation between T2DM and MCI, achieve the purpose of early disease prediction, and provide new ideas for the prevention and treatment of dementia. We downloaded T2DM and MCI microarray data from GEO databases and identified the differentially expressed genes associated with MCI and T2DM. We obtained co-expressed genes by intersecting differentially expressed genes. Then, we performed GO and KEGG enrichment analysis of co-DEGs. Next, we constructed the PPI network and found the hub genes in the network. By constructing the ROC curve of hub genes, the most valuable genes for diagnosis were obtained. Finally, the correlation between MCI and T2DM was clinically verified by means of a current situation investigation, and the hub gene was verified by qRT-PCR. A total of 214 co-DEGs were selected, 28 co-DEGs were up-regulated, and 90 co-DEGs were down-regulated. Functional enrichment analysis showed that co-DEGs were mainly enriched in metabolic diseases and some signaling pathways. The construction of the PPI network identified the hub genes in MCI and T2DM co-expression genes. We identified nine hub genes of co-DEGs, namely LNX2, BIRC6, ANKRD46, IRS1, TGFB1, APOA1, PSEN1, NPY, and ALDH2. Logistic regression analysis and person correlation analysis showed that T2DM was correlated with MCI, and T2DM increased the risk of cognitive impairment. The qRT-PCR results showed that the expressions of LNX2, BIRC6, ANKRD46, TGFB1, PSEN1, and ALDH2 were consistent with the results of bioinformatic analysis. This study screened the co-expressed genes of MCI and T2DM, which may provide new therapeutic targets for the diagnosis and treatment of diseases.

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“…As a result, it restores Aβ spatial arrangement and cognition in AD, because of the fact that APP plays a significant role in the sequential proteolytic cleavages that result in the generation of Aβ-peptides. Mutations in APP genes such as presenilin-1 and presenilin-2 and APO-ε4 are implicated in the pathology of AD [ 104 ].…”

Section: Types Of Brain Disordersmentioning

confidence: 99%

Mechanistic Insights, Treatment Paradigms, and Clinical Progress in Neurological Disorders: Current and Future Prospects

Alkahtani

AL–Johani

Alarifi

2023

IJMS

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Neurodegenerative diseases (NDs) are a major cause of disability and are related to brain development. The neurological signs of brain lesions can vary from mild clinical shortfalls to more delicate and severe neurological/behavioral symptoms and learning disabilities, which are progressive. In this paper, we have tried to summarize a collective view of various NDs and their possible therapeutic outcomes. These diseases often occur as a consequence of the misfolding of proteins post-translation, as well as the dysfunctional trafficking of proteins. In the treatment of neurological disorders, a challenging hurdle to cross regarding drug delivery is the blood–brain barrier (BBB). The BBB plays a unique role in maintaining the homeostasis of the central nervous system (CNS) by exchanging components between the circulations and shielding the brain from neurotoxic pathogens and detrimental compounds. Here, we outline the current knowledge about BBB deterioration in the evolving brain, its origin, and therapeutic interventions. Additionally, we summarize the physiological scenarios of the BBB and its role in various cerebrovascular diseases. Overall, this information provides a detailed account of BBB functioning and the development of relevant treatments for neurological disorders. This paper will definitely help readers working in the field of neurological scientific communities.

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Genetics, Functions, and Clinical Impact of Presenilin-1 (PSEN1) Gene

Cited by 39 publications

References 303 publications

The structure of an Amyloid Precursor Protein/talin complex indicates a mechanical basis of Alzheimer's Disease.

The structure of an Amyloid Precursor Protein/talin complex indicates a mechanical basis of Alzheimer's Disease.

Exploration and Clinical Verification of the Blood Co-Expression Genes of Type 2 Diabetes Mellitus and Mild Cognitive Dysfunction in the Elderly

Mechanistic Insights, Treatment Paradigms, and Clinical Progress in Neurological Disorders: Current and Future Prospects

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