Biology subjects

Battaglia, R. A.

Publications and source records attributed to Battaglia, R. A..

4 recordsLinked to original sources

bioRxiv2026

The defining features of intrinsic transcription terminators

Transcription terminators are universal landmarks that delimit RNAs and tune downstream gene expression, yet the sequence rules that define them remain elusive. The classical model of bacterial intrinsic termination--an RNA hairpin followed by a uracil-rich tract--is incomplete, as stem-preserving mutations can abolish termination. By precisely mapping termination sites across 104 sequences, we uncovered a previously unresolved feature required for intrinsic termination: dinucleotides positioned at both edges of the transcription bubble, resembling the elemental RNA polymerase pause signal. Together, hairpin, U-tract and bubble-edge sequences (HUB) account for most variation in termination efficiency and pinpoint bona fide terminators across diverse bacterial phyla. These findings establish HUB as the defining element of intrinsic terminators and provide a framework for decoding and engineering gene expression across genomes.

molecular biology↗

bioRxiv2025

Gene editing in "cell villages" enables exploring disease-relevant mutations in many genetic backgrounds

Understanding how individual genetic backgrounds shape the effects of disease-associated mutations is central to elucidating the biology of complex psychiatric disorders. We developed a scalable village editing strategy that enables simultaneous genome editing across multiple induced pluripotent stem cell (iPSC) lines, allowing systematic assessment of how polygenic context modulates the impact of specific mutations. Using pooled CRISPR editing in 15 iPSC lines spanning a range of schizophrenia (SCZ) polygenic risk scores, we generated homozygous and heterozygous knockouts in two known SCZ-associated genes: LRP1, involved in cholesterol import, and NRXN1, a presynaptic adhesion molecule. By mixing all lines prior to editing and de-multiplexing them afterward, we efficiently produced multi-donor knockout neurons at scale. Transcriptomic profiling revealed that LRP1 and NRXN1 loss produce both shared and donor-specific effects on neuronal gene expression, with variable perturbation of neurotransmitter transport and cholesterol biosynthesis pathways across genetic backgrounds. These results demonstrate that village editing enables systematic dissection of gene-background interactions in human neurons, offering a powerful framework for studying the polygenic architecture of psychiatric disease.

cell biology↗

bioRxiv2024

Gigaxonin, mutated in Giant Axonal Neuropathy, interacts with TDP-43 and other RNA binding proteins

Giant Axonal Neuropathy (GAN) is a neurodegenerative disease caused by loss-of-function mutations in the KLHL16 gene, encoding the cytoskeleton regulator gigaxonin. In the absence of functional gigaxonin, intermediate filament (IF) proteins accumulate in neurons and other cell types due to impaired turnover and transport. GAN neurons exhibit distended, swollen axons and distal axonal degeneration, but the mechanisms behind this selective neuronal vulnerability are unknown. Our objective was to identify novel gigaxonin interactors pertinent to GAN neurons. Unbiased proteomics revealed a statistically significant predominance of RNA-binding proteins (RBPs) within the soluble gigaxonin interactome and among differentially-expressed proteins in iPSC-neuron progenitors from a patient with classic GAN. Among the identified RBPs was TAR DNA-binding protein 43 (TDP-43), which associated with the gigaxonin protein and its mRNA transcript. TDP-43 co-localized within large axonal neurofilament IFs aggregates in iPSC-motor neurons derived from a GAN patient with the axonal CMT-plus disease phenotype. Our results implicate RBP dysfunction as a potential underappreciated contributor to GAN-related neurodegeneration. SummaryThis work reveals that the neurodegeneration-associated protein and cytoskeleton regulator gigaxonin and its mRNA associate with numerous RNA binding proteins. These findings shift understanding of normal gigaxonin function and provide insights into how disease-causing mutations in the gigaxonin-encoding gene (KLHL16) may ignite a pathogenic cascade in neurons.

cell biology↗

bioRxiv2023

Integrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging

A{beta} peptides derived from the amyloid precursor protein (APP) have been strongly implicated in the pathogenesis of Alzheimers disease. However, the normal function of APP and the importance of that role in neurodegenerative disease is less clear. We recovered the Drosophila ortholog of APP, Appl, in an unbiased forward genetic screen for neurodegeneration mutants. We performed comprehensive single cell transcriptional and proteomic studies of Appl mutant flies to investigate Appl function in the aging brain. We found an unexpected role for Appl in control of multiple cellular pathways, including translation, mitochondrial function, nucleic acid and lipid metabolism, cellular signaling and proteostasis. We mechanistically defined a role for Appl in regulating autophagy through TGF{beta} signaling and documented the broader relevance of our findings using mouse genetic, human iPSC and in vivo tauopathy models. Our results demonstrate a conserved role for APP in controlling age-dependent proteostasis with plausible relevance to Alzheimers disease.

neuroscience↗