Biology subjects

Aldrich, A.

Publications and source records attributed to Aldrich, A..

3 recordsLinked to original sources

bioRxiv2026

Gateway: patient olfactory neurons for large-scale discovery in neurodegenerative disease

An estimated 42% of Americans over age 55 will develop dementia, but the molecular understanding of dementia and neurodegenerative disease is constrained because the living human brain cannot be routinely sampled during disease progression. Olfactory sensory neurons provide a clinically accessible neuronal tissue source with developmental, transcriptional, and disease-relevant links to the central nervous system. Here we describe Gateway, a platform that combines device guided olfactory epithelium biopsy, onsite fixation, and 10x Genomics FLEX RNA profiling to generate single-cell transcriptomic data from living patient neurons. We present a 4-million-cell atlas representing 202 human donors, including healthy controls and individuals with neurodegenerative diseases, and release it as an open resource through CELLxGENE. We define the cellular composition of the human olfactory epithelium and show that Gateway captures neuronal functional and compartmental programs and detects more brain-enriched genes than other clinically accessible transcriptomic sample types. In exploratory analyses of Alzheimers Disease and Parkinsons Disease, we identify dys-regulation of pathways and GWAS-implicated genes related to key neurodegenerative mechanisms such as neuroinflammation, endolysosomal biology, proteostasis, and synaptic maintenance. Together, this atlas and clinical workflow establish living patient olfactory neurons as a scalable complementary modality for neuroscience research, target discovery, and biomarker development in neurodegenerative disease.

neuroscience↗

bioRxiv2026

Proteolytic dissection of eIF4G reveals the closed-loop mRNP as an architecture for translation repression.

Formation of a "closed-loop" mRNP, in which the 5' cap and 3' poly(A) tail are bridged by eIF4E-eIF4G-PABP interactions, has long been proposed to drive efficient translation initiation. Direct tests of this model in mammalian cells have remained elusive. Using auxin-inducible degron (AID) technology to acutely deplete eIF4G1, we find that global translation is only partially reduced and recovers without restoration of eIF4G1 levels. We identify eIF4G3 as an underappreciated contributor to basal translation that buffers translational output upon eIF4G1 loss without increased protein expression, explaining the modest defects observed in prior RNAi-based studies. Systematic replacement of eIF4G1 with defined cleavage products and interaction mutants reveals that PABP binding by eIF4G1 is dispensable for bulk translation initiation: the central caspase-3 cleavage fragment of eIF4G1 (casp3-cpM), which lacks the PABP-interaction domain, fully rescues global protein synthesis, and acute depletion of both major cytoplasmic PABP paralogs primarily destabilizes mRNAs rather than impairing initiation. In contrast, the N-terminal enteroviral 2A cleavage product (2A-cpN) is a potent, dominant translational repressor that requires simultaneous eIF4E and PABP engagement to form a dead-end closed-loop mRNP that sequesters initiation factors without enabling 43S recruitment. These findings reveal that the eIF4G-PABP closed-loop architecture is not required for productive initiation but can be actively co-opted for translational silencing. This explains why viral eIF4G cleavage, but not factor depletion, produces near-complete translational shutoff. The modular architecture of eIF4G enables diametrically opposing translational outcomes through selective proteolytic processing.

molecular biology↗

bioRxiv2025

Metal stress uncouples early pre-rRNA processing from ISR activation and reveals flexible checkpoints in human ribosome biogenesis

Ribosome synthesis is one of the most energy-intensive processes in a growing cell, consuming more than 60% of cellular energy reserves. As such, ribosome biogenesis is highly sensitive to stress to prevent costly expenditures under adverse conditions. Moreover, successful assembly requires precise stoichiometric balance between ribosomal proteins and ribosomal RNAs. Here, we define novel regulatory mechanisms of ribosome biogenesis under stress that reveal previously unrecognized aspects of rRNA maturation. We demonstrate that early pre-rRNA processing is particularly sensitive to stress induced by environmentally relevant heavy metals. Surprisingly, our analysis shows that 5' and 3' end processing can be uncoupled in human cells, with 3' end cleavage occurring independently of 5' end processing. We further show that classical inducers of endoplasmic reticulum stress suppress ribosomal protein synthesis without inhibiting rRNA transcription, leading to an imbalance between these essential components of ribosome assembly. This imbalance may exacerbate cellular stress and compromise proteostasis. Together, our findings uncover stress-specific checkpoints in ribosome biogenesis that link environmental exposures to disrupted nucleolar function and highlight new layers of regulation in human rRNA maturation.

biochemistry↗