Genetic dependency of Alzheimer’s disease-associated genes across cells and tissue types

Jaladanki, Suraj; Elmas, Abdulkadir; Malave, Gabriel Santos; Huang, Kuan‐lin

doi:10.1038/s41598-021-91713-2

Cited by 6 publications

(7 citation statements)

References 28 publications

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“…An essential score closer to − 0.5 represents knockdown-dependent depletion, indicating higher essentiality for cell proliferation and a score closer to − 1 represents knockdown-dependent obliteration, implying high essentiality and a positive score may indicate cell proliferation. In cancer research, it is promising to target the genes with low essential scores, whereas a neurodegeneration study should target genes non-essential for cell proliferation with high essential scores hypothetically [ 39 ]. Our screening of 117 cell lines of nervous system lineage showed that GLS had a high essential score as observed in [ 39 ], confirming glutaminase targetability in the brain.…”

Section: Resultsmentioning

confidence: 99%

“…In cancer research, it is promising to target the genes with low essential scores, whereas a neurodegeneration study should target genes non-essential for cell proliferation with high essential scores hypothetically [ 39 ]. Our screening of 117 cell lines of nervous system lineage showed that GLS had a high essential score as observed in [ 39 ], confirming glutaminase targetability in the brain. Supporting this, GLS knockdown was not predicted to inhibit cell proliferation necessarily in other tissues (n = 371) (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Drug repositioning targeting glutaminase reveals drug candidates for the treatment of Alzheimer’s disease patients

Bayraktar

Kim

et al. 2023

J Transl Med

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Background Despite numerous clinical trials and decades of endeavour, there is still no effective cure for Alzheimer's disease. Computational drug repositioning approaches may be employed for the development of new treatment strategies for Alzheimer’s patients since an extensive amount of omics data has been generated during pre-clinical and clinical studies. However, targeting the most critical pathophysiological mechanisms and determining drugs with proper pharmacodynamics and good efficacy are equally crucial in drug repurposing and often imbalanced in Alzheimer’s studies. Methods Here, we investigated central co-expressed genes upregulated in Alzheimer’s disease to determine a proper therapeutic target. We backed our reasoning by checking the target gene’s estimated non-essentiality for survival in multiple human tissues. We screened transcriptome profiles of various human cell lines perturbed by drug induction (for 6798 compounds) and gene knockout using data available in the Connectivity Map database. Then, we applied a profile-based drug repositioning approach to discover drugs targeting the target gene based on the correlations between these transcriptome profiles. We evaluated the bioavailability, functional enrichment profiles and drug-protein interactions of these repurposed agents and evidenced their cellular viability and efficacy in glial cell culture by experimental assays and Western blotting. Finally, we evaluated their pharmacokinetics to anticipate to which degree their efficacy can be improved. Results We identified glutaminase as a promising drug target. Glutaminase overexpression may fuel the glutamate excitotoxicity in neurons, leading to mitochondrial dysfunction and other neurodegeneration hallmark processes. The computational drug repurposing revealed eight drugs: mitoxantrone, bortezomib, parbendazole, crizotinib, withaferin-a, SA-25547 and two unstudied compounds. We demonstrated that the proposed drugs could effectively suppress glutaminase and reduce glutamate production in the diseased brain through multiple neurodegeneration-associated mechanisms, including cytoskeleton and proteostasis. We also estimated the human blood–brain barrier permeability of parbendazole and SA-25547 using the SwissADME tool. Conclusions This study method effectively identified an Alzheimer’s disease marker and compounds targeting the marker and interconnected biological processes by use of multiple computational approaches. Our results highlight the importance of synaptic glutamate signalling in Alzheimer’s disease progression. We suggest repurposable drugs (like parbendazole) with well-evidenced activities that we linked to glutamate synthesis hereby and novel molecules (SA-25547) with estimated mechanisms for the treatment of Alzheimer’s patients.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Drug repositioning targeting glutaminase reveals drug candidates for the treatment of Alzheimer’s disease patients

Bayraktar

Kim

et al. 2023

J Transl Med

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“…In Supplementary Table II Above, we mentioned MMP9 as an example of genes playing opposite roles in GBM and AD. The UBE2C protein-coding gene is another known gene with this characteristic [38,39]. Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Above, we mentioned MMP9 as an example of these genes. The UBE2C protein-coding gene is another example [27,28]. Fig.…”

Section: Resultsmentioning

confidence: 99%

A bird’s eye view to the homeostatic, Alzheimer and Glioblastoma attractors

Nieves,

Gil,

Gonzalez

2023

Preprint

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A well known paradigm in molecular genetics expresses that local maxima of fitness in gene expression space are related to biological viable states [1]. This picture has been applied to the description of cell fates along differentiation lines [2]. However, to the best of our knowledge, there are no plots based on real data for a given tissue representing at least a partial landscape with more than two of these maxima. We provide a drawing for white matter of the brain in which the normal state is represented along with the glioblastoma (GBM) attractor and the seemingly modest maximum related to Alzheimer disease (AD). The plot shows that GBM and AD are opposite alternatives, as epidemiological [3,4,5,6] and molecular biology studies [7,8,9] suggest, and indicates a path or corridor for normal aging, in accordance with the programmatic aging theory [10,11]. At the gene level, there are genes varying in the same way in the aging, AD progression and cancer processes, whereas there are also genes indicating the disjunctive between AD and GBM. An example of the latter is the MMP9 protein-coding gene, playing an important role in tumor invasion [12,13], but known also as a neuroprotector, controlling the interactions between axons and beta-amyloid fibers [14]. Deviations of the gene expression value from its reference in normal tissue may indicate either a potential progression to AD (under-expression) or to GBM (over-expression). This unusual view, following from a simple plot, may help understand the relations between AD and GBM biology and identify useful gene markers for both processes. We anticipate that similar diagrams could be important in other tissues.

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“…In mammals, mutations in Timeless and other circadian genes have been linked to cognitive disorders such as autism, schizophrenia, bipolar disorder, and Alzheimer’s disease. 19 – 23 More specifically, in humans, Timeless mutations provoke cytoplasmatic accumulation, which destabilizes the interaction of PER2 and CRY2, resulting in familial advanced sleep phase (FASP) disorder. 24 Importantly, TIMELESS contains a DNA binding domain implicated in DNA damage repair 25 – 27 and is essential during embryonic development.…”

Section: Introductionmentioning

confidence: 99%

Circadian protein TIMELESS regulates synaptic function and memory by modulating cAMP signaling

Barrio-Alonso¹,

Lituma²,

Notaras³

et al. 2023

Cell Reports

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Genetic dependency of Alzheimer’s disease-associated genes across cells and tissue types

Cited by 6 publications

References 28 publications

Drug repositioning targeting glutaminase reveals drug candidates for the treatment of Alzheimer’s disease patients

Drug repositioning targeting glutaminase reveals drug candidates for the treatment of Alzheimer’s disease patients

A bird’s eye view to the homeostatic, Alzheimer and Glioblastoma attractors

Circadian protein TIMELESS regulates synaptic function and memory by modulating cAMP signaling

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