<i>ZCWPW1</i>loss-of-function variants in Alzheimer’s Disease

Küçükali, Fahri; Nußbaumer, Katrin; Dongen, Jasper Van; Hens, Elisabeth; Bellenguez, Céline; Grenier‐Boley, Benjamin; Daian, Delphine; Boland, Anne; Deleuze, Jean-François; Lambert, Jean‐Charles; Broeckhoven, Christine Van; Sleegers, Kristel

doi:10.1101/2021.08.13.21261426

Cited by 3 publications

(1 citation statement)

References 75 publications

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“…MS4A6A (i.e., membranespanning 4-domains, subfamily A, member 6A), susceptibility loci of Alzheimer's disease, was found to be related to the volume loss of middle temporal, precuneus, and entorhinal in the brain (Ma, 2016). ZCWPW1 (i.e., Zinc Finger CW-Type and PWWP Domain Containing 1), a histone modification reader that is involved in epigenetic regulation, was reported for strong association with late-onset Alzheimer's disease in several reports (Rosenthal and Kamboh, 2014;Gao, 2016;Karch, 2016;Küçükali, 2021). CLU (i.e., clusterin) could bind amyloid-β peptides and prevent fibril formation, a hallmark of AD pathology (Wojtas, 2020).…”

Section: Figurementioning

confidence: 99%

A computational framework for identifying chemical compounds to bind Apolipoprotein E4 for Alzheimer’s disease intervention

et al. 2023

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Alzheimer’s disease (AD), a neurodegenerative disorder, is characterized by its ability to cause memory loss and damage other cognitive functions. Aggregation of amyloid beta (Aβ) plaques and neurofibrillary tangles in the brain are responsible for the development of Alzheimer’s disease (AD). While attempts targeting Aβ and tau proteins have been extensively conducted in the past decades, only two FDA-approved drugs (i.e., monoclonal antibodies) tackle the underlying biology of Alzheimer’s disease. In this study, an integrated computational framework was developed to identify new drug targets for Alzheimer’s disease and identify small molecules as potential therapeutical options. A systematic investigation of the gene networks firstly revealed that the Apolipoprotein E4 (ApoE4) gene plays a central role among genes associated with Alzheimer’s disease. The ApoE4 protein was then chosen as the protein target based on its role in the main pathological hallmarks of AD, which has been shown to increase Aβ accumulation by directly binding to Aβ as well as interfering with Aβ clearance that is associated with other receptors. A library of roughly 1.5 million compounds was then virtually screened via a ligand-protein docking program to identify small-molecule compounds with potential binding capacity to the ApoE4 N-terminal domain. On the basis of compound properties, 312 compounds were selected, analyzed and clustered to further identify common structures and essential functional groups that play an important role in binding ApoE4. The in silico prediction suggested that compounds with four common structures of sulfon-amine-benzene, 1,2-benzisothiazol-3-amine 1,1-dioxide, N-phenylbenzamide, and furan-amino-benzene presented strong hydrogen bonds with residues E27, W34, R38, D53, D153, or Q156 in the N terminal of ApoE4. These structures might also form strong hydrophobic interactions with residues W26, E27, L28, L30, G31, L149, and A152. While the 312 compounds can serve as drug candidates for further experiment assays, the four common structures, along with the residues for hydrogen bond or hydrophobic interaction, pave the foundation to further optimize the compounds as better binders of ApoE4.

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Section: Figurementioning

confidence: 99%

A computational framework for identifying chemical compounds to bind Apolipoprotein E4 for Alzheimer’s disease intervention

et al. 2023

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The relationship of early- and late-onset Alzheimer’s disease genes with COVID-19

2022

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Individuals with Alzheimer’s disease and other neurodegenerative diseases have been exposed to excess risk by the COVID-19 pandemic. COVID-19’s main manifestations include high body temperature, dry cough, and exhaustion. Nevertheless, some affected individuals may have an atypical presentation at diagnosis but suffer neurological signs and symptoms as the first disease manifestation. These findings collectively show the neurotropic nature of SARS-CoV-2 virus and its ability to involve the central nervous system. In addition, Alzheimer’s disease and COVID-19 has a number of common risk factors and comorbid conditions including age, sex, hypertension, diabetes, and the expression of APOE ε4. Until now, a plethora of studies have examined the COVID-19 disease but only a few studies has yet examined the relationship of COVID-19 and Alzheimer’s disease as risk factors of each other. This review emphasizes the recently published evidence on the role of the genes of early- or late-onset Alzheimer’s disease in the susceptibility of individuals currently suffering or recovered from COVID-19 to Alzheimer’s disease or in the susceptibility of individuals at risk of or with Alzheimer’s disease to COVID-19 or increased COVID-19 severity and mortality. Furthermore, the present review also draws attention to other uninvestigated early- and late-onset Alzheimer’s disease genes to elucidate the relationship between this multifactorial disease and COVID-19.

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Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and informs causal proteins for Alzheimer’s disease

Cruchaga,

Western,

Timsina

et al. 2023

Preprint

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The integration of quantitative trait loci (QTL) with disease genome-wide association studies (GWAS) has proven successful at prioritizing candidate genes at disease-associated loci. QTL mapping has mainly been focused on multi-tissue expression QTL or plasma protein QTL (pQTL). Here we generated the largest-to-date cerebrospinal fluid (CSF) pQTL atlas by analyzing 7,028 proteins in 3,107 samples. We identified 3,373 independent study-wide associations for 1,961 proteins, including 2,448 novel pQTLs of which 1,585 are unique to CSF, demonstrating unique genetic regulation of the CSF proteome. In addition to the established chr6p22.2-21.32 HLA region, we identified pleiotropic regions on chr3q28 near OSTN and chr19q13.32 near APOE that were enriched for neuron-specificity and neurological development. We also integrated this pQTL atlas with the latest Alzheimer’s disease (AD) GWAS through PWAS, colocalization and Mendelian Randomization and identified 42 putative causal proteins for AD, 15 of which have drugs available. Finally, we developed a proteomics-based risk score for AD that outperforms genetics-based polygenic risk scores. These findings will be instrumental to further understand the biology and identify causal and druggable proteins for brain and neurological traits.

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ZCWPW1loss-of-function variants in Alzheimer’s Disease

Cited by 3 publications

References 75 publications

A computational framework for identifying chemical compounds to bind Apolipoprotein E4 for Alzheimer’s disease intervention

A computational framework for identifying chemical compounds to bind Apolipoprotein E4 for Alzheimer’s disease intervention

The relationship of early- and late-onset Alzheimer’s disease genes with COVID-19

Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and informs causal proteins for Alzheimer’s disease

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