Biology subjects

Danquah, S.

Publications and source records attributed to Danquah, S..

4 recordsLinked to original sources

bioRxiv2025

CellFIE: Integrating Pathway Discovery With Pooled Profiling of Perturbations Uncovers Pathways of Huntington's Disease, Including Genetic Modifiers of Neuronal Development and Morphology

Genomic screens and GWAS are powerful tools for identifying disease-modifying genes, but it is often challenging to understand the pathways by which these genes function. Here, we take an integrated approach that combines network analysis and an imaging-based pooled genetic perturbation study to examine modifiers of Huntingtons disease (HD). The computational analysis highlighted several genes in a subnetwork enriched for modifiers of neuronal development and morphology. To test the functional roles of these genes, we developed an experimental pipeline that allows pooled CRISPRi KD of 21 genes in human iPSC-derived neurons followed by optical analysis of genotypes, neuronal arborization, multiplexed pathway activity and morphological fingerprint readout. This approach recovered known genes involved in morphology and confirmed unexpected links from the network between several genetic modifiers of HD and morphology. Our approach overcomes challenges in pooled measurement of neuronal function and health and could be adapted for other phenotypes in HD and other neurological diseases.

neuroscience↗

bioRxiv2025

Succinate Dehydrogenase loss causes cascading metabolic effects that impair pyrimidine biosynthesis

Decreased availability of the amino acid aspartate can constrain cell function in diverse biological contexts, but the temporal interplay between aspartate, downstream metabolic changes, and functional effects remains poorly understood. Using an aspartate biosensor and live-cell imaging, we examine the interaction between aspartate abundance and cell proliferation in several models of aspartate limitation. While aspartate deficiencies intuitively interface with proliferation in some contexts, aspartate limitation from succinate dehydrogenase (SDH) inhibition causes strikingly nonintuitive dynamics resulting from an outsized impairment of pyrimidine synthesis. Mechanistically, we find that SDH loss impairs pyrimidine biosynthesis by decreasing aspartate and accumulating succinate, which competitively inhibits mammalian aspartate transcarbamylase (ATCase). This metabolic interaction persists in multiple models of SDH deficiency, causing pyrimidine insufficiency, replication stress, and sensitivity to ATR kinase inhibition. These findings define a novel role for succinate in modulating cellular nucleotide homeostasis, suggest a potential therapeutic vulnerability of SDH-deficient tumors, and demonstrate how cascading metabolic interactions can unfold to impact cell function.

cell biology↗

bioRxiv2024

A systems-biology approach connects aging mechanisms with Alzheimer's disease pathogenesis

Despite years of intense investigation, the mechanisms underlying neuronal death in Alzheimers disease, the most common neurodegenerative disorder, remain incompletely understood. To define relevant pathways, we integrated the results of an unbiased, genome-scale forward genetic screen for age-associated neurodegeneration in Drosophila with human and Drosophila Alzheimers disease-associated multi-omics. We measured proteomics, phosphoproteomics, and metabolomics in Drosophila models of Alzheimers disease and identified Alzheimers disease human genetic variants that modify expression in disease-vulnerable neurons. We used a network optimization approach to integrate these data with previously published Alzheimers disease multi-omic data. We computationally predicted and experimentally demonstrated how HNRNPA2B1 and MEPCE enhance tau-mediated neurotoxicity. Furthermore, we demonstrated that the screen hits CSNK2A1 and NOTCH1 regulate DNA damage in Drosophila and human iPSC-derived neural progenitor cells. Our work identifies candidate pathways that could be targeted to ameliorate neurodegeneration in Alzheimers disease.

systems biology↗

bioRxiv2023

Simultaneous CRISPR screening and spatial transcriptomics reveals intracellular, intercellular, and functional transcriptional circuits.

Pooled optical screens have enabled the study of cellular interactions, morphology, or dynamics at massive scale, but have not yet leveraged the power of highly-plexed single-cell resolved transcriptomic readouts to inform molecular pathways. Here, we present Perturb-FISH, which bridges these approaches by combining imaging spatial transcriptomics with parallel optical detection of in situ amplified guide RNAs. We show that Perturb-FISH recovers intracellular effects that are consistent with Perturb-seq results in a screen of lipopolysaccharide response in cultured monocytes, and uncover new intercellular and density-dependent regulation of the innate immune response. We further pair Perturb-FISH with a functional readout in a screen of autism spectrum disorder risk genes, showing common calcium activity phenotypes in induced pluripotent stem cell derived astrocytes and their associated genetic interactions and dysregulated molecular pathways. Perturb-FISH is thus a generally applicable method for studying the genetic and molecular associations of spatial and functional biology at single-cell resolution.

genomics↗