Biology subjects

Im, E.

Publications and source records attributed to Im, E..

3 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↗

bioRxiv2022

Lysosomal dysfunction in Down Syndrome and Alzheimer mouse models is caused by selective v-ATPase inhibition by Tyr682 phosphorylated APP βCTF

Lysosome dysfunction arises early and propels Alzheimers Disease (AD). Herein, we show that amyloid precursor protein (APP), linked to early-onset AD in Down Syndrome (DS), acts directly via its {beta}-C-terminal fragment ({beta}CTF) to disrupt lysosomal v-ATPase and acidification. In human DS fibroblasts, the phosphorylated 682YENPTY internalization motif of APP-{beta}CTF binds selectively within a pocket of the v-ATPase V0a1 subunit cytoplasmic domain and competitively inhibits association of the V1 subcomplex of v-ATPase, thereby reducing its activity. Lowering APP-{beta}CTF Tyr682 phosphorylation restores v-ATPase and lysosome function in DS fibroblasts and in vivo in brains of DS model mice. Notably, lowering APP-{beta}CTF Tyr682 phosphorylation below normal constitutive levels boosts v-ATPase assembly and activity, suggesting that v-ATPase may also be modulated tonically by phospho-APP-{beta}CTF. Elevated APP-{beta}CTF Tyr682 phosphorylation in two mouse AD models similarly disrupts v-ATPase function. These findings offer new insight into the pathogenic mechanism underlying faulty lysosomes in all forms of AD.

neuroscience↗

bioRxiv2021

The three-dimensional landscape of chromatin accessibility in Alzheimer's disease

Much is still unknown about the neurobiology of Alzheimers disease (AD). To better understand AD, we generated 636 ATAC-seq libraries from cases and controls to construct detailed genomewide chromatin accessibility maps of neurons and non-neurons from two AD-affected brain regions, the entorhinal cortex and superior temporal gyrus. By analyzing a total of 19.6 billion read pairs, we expanded the known repertoire of regulatory sequences in the human brain. Multi-omic data integration associated global patterns of chromatin accessibility with gene expression and identified cell-specific enhancer-promoter interactions. Using inter-individual variation in chromatin accessibility, we define cis-regulatory domains capturing the 3D structure of the genome. Multifaceted analyses uncovered disease associated perturbations impacting chromatin accessibility, transcription factor regulatory networks and the 3D genome, and implicated transcriptional dysregulation in AD. Overall, we applied a systematic approach to understand the role of the 3D genome in AD and to illuminate novel disease biology that can advance diagnosis and therapy.

neuroscience↗