Trae Dunn

All Publications

• The molecular basis for nuclear pore destruction by a proximity-inducing molecular glue. Cell chemical biology Hinshaw, S. M., Yuan, L., Noman, M. A., Martinez, M. J., Colombo, G. M., Dwyer, B. G., Ji, W., Romero, B. A., Forrest, I., Lu, J., Bian, J., Dunn, T. B., Garvin, E. R., Fernandez, D., Zhang, T., Gray, N. S., Corsello, S. M. 2026

  Abstract

  Molecular glues that induce new protein interactions can be potent therapeutics. We and others recently discovered that the small molecule PRLX-93936 (PRLX), which was originally developed as an erastin derivative with antitumor activity, is a molecular glue that alters the substrate specificity of the TRIM21 ubiquitin ligase. PRLX causes TRIM21 to bind the nuclear pore protein NUP98, triggering nuclear pore complex (NPC) degradation. We present here the structural and biochemical basis of NUP98 recognition, finding that ternary complex assembly depends on the creation of a composite TRIM21-small molecule surface competent for NUP98 binding. A scarcity of direct small molecule-NUP98 contacts likely explains how multiple structurally diverse TRIM21 ligands can induce NPC degradation. We also report the discovery of an enhanced molecular glue, MAN-021, and describe its structure. Our findings provide a basis for rational development of next-generation small molecules with enhanced or differentiated activities.

  View details for DOI 10.1016/j.chembiol.2026.04.016

  View details for PubMedID 42202785

• ConvNeXt-Driven Detection of Alzheimer's Disease: A Benchmark Study on Expert-Annotated AlzaSet MRI Dataset Across Anatomical Planes. Diagnostics (Basel, Switzerland) Basereh, M., Abikenari, M. A., Sadeghzadeh, S., Dunn, T., Freichel, R., Siddarth, P., Ghahremani, D., Lavretsky, H., Buch, V. P. 2025; 15 (23)

  Abstract

  Background: Alzheimer's disease (AD) is a leading worldwide cause of cognitive impairment, necessitating accurate, inexpensive diagnostic tools to enable early recognition. Methods: In this study, we present a robust deep learning approach for AD classification based on structural MRI scans, ConvNeXt, an emergent convolutional architecture inspired by vision transformers. We introduce AlzaSet, a clinically curated T1-weighted MRI dataset of 79 subjects (63 with Alzheimer's disease [AD], 16 cognitively normal controls [NC]) acquired on a 1.5 T Siemens Aera in axial, coronal, and sagittal planes, respectively (12,947 slices in total). Images are neuroradiologist-labeled. Results are reported per plane, with awareness of the class imbalance at the subject level. We further present AlzaSet, a novel, expertly labeled clinical dataset with axial, coronal, and sagittal perspectives from AD and cognitively normal control subjects. Three ConvNeXt sizes (Tiny, Small, Base) were compared and benchmarked against existing state-of-the-art CNN models (VGG16, VGG19, InceptionV3, DenseNet121). Results: ConvNeXt-Base consistently outperformed the other models on coronal slices with an accuracy of 98.37% and an AUC of 0.992. Coronal views were determined to be most diagnostically informative, with emphasis on visualization of the medial temporal lobe. Moreover, comparison with recent ensemble-based techniques showed superior performance with comparable computational efficiency. Conclusions: These results indicate that ConvNeXt-capable models applied to clinically curated datasets have strong potential to provide scalable, real-time AD screening in diverse settings, including both high-resource and resource-constrained settings.

  View details for DOI 10.3390/diagnostics15232997

  View details for PubMedID 41374378

• Development of small-molecule Tau-SH3 interaction inhibitors that prevent amyloid-β toxicity and network hyperexcitability. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics Roth, J. R., Rush, T., Thompson, S. J., Aldaher, A. R., Dunn, T. B., Mesina, J. S., Cochran, J. N., Boyle, N. R., Dean, H. B., Yang, Z., Pathak, V., Ruiz, P., Wu, M., Day, J. J., Bostwick, J. R., Suto, M. J., Augelli-Szafran, C. E., Roberson, E. D. 2024; 21 (1): e00291

  Abstract

  Alzheimer's disease (AD) is the leading cause of dementia and lacks highly effective treatments. Tau-based therapies hold promise. Tau reduction prevents amyloid-β-induced dysfunction in preclinical models of AD and also prevents amyloid-β-independent dysfunction in diverse disease models, especially those with network hyperexcitability, suggesting that strategies exploiting the mechanisms underlying Tau reduction may extend beyond AD. Tau binds several SH3 domain-containing proteins implicated in AD via its central proline-rich domain. We previously used a peptide inhibitor to demonstrate that blocking Tau interactions with SH3 domain-containing proteins ameliorates amyloid-β-induced dysfunction. Here, we identify a top hit from high-throughput screening for small molecules that inhibit Tau-FynSH3 interactions and describe its optimization with medicinal chemistry. The resulting lead compound is a potent cell-permeable Tau-SH3 interaction inhibitor that binds Tau and prevents amyloid-β-induced dysfunction, including network hyperexcitability. These data support the potential of using small molecule Tau-SH3 interaction inhibitors as a novel therapeutic approach to AD.

  View details for DOI 10.1016/j.neurot.2023.10.001

  View details for PubMedID 38241154

  View details for PubMedCentralID PMC10903085

• cnd-1/NeuroD1 Functions with the Homeobox Gene ceh-5/Vax2 and Hox Gene ceh-13/labial To Specify Aspects of RME and DD Neuron Fate in Caenorhabditis elegans. G3 (Bethesda, Md.) Aquino-Nunez, W., Mielko, Z. E., Dunn, T., Santorella, E. M., Hosea, C., Leitner, L., McCalla, D., Simms, C., Verola, W. M., Vijaykumar, S., Hudson, M. L. 2020; 10 (9): 3071-3085

  Abstract

  Identifying the mechanisms behind neuronal fate specification are key to understanding normal neural development in addition to neurodevelopmental disorders such as autism and schizophrenia. In vivo cell fate specification is difficult to study in vertebrates. However, the nematode Caenorhabditis elegans, with its invariant cell lineage and simple nervous system of 302 neurons, is an ideal organism to explore the earliest stages of neural development. We used a comparative transcriptome approach to examine the role of cnd-1/NeuroD1 in C. elegans nervous system development and function. This basic helix-loop-helix transcription factor is deeply conserved across phyla and plays a crucial role in cell fate specification in both the vertebrate nervous system and pancreas. We find that cnd-1 controls expression of ceh-5, a Vax2-like homeobox class transcription factor, in the RME head motorneurons and PVQ tail interneurons. We also show that cnd-1 functions redundantly with the Hox gene ceh-13/labial in defining the fate of DD1 and DD2 embryonic ventral nerve cord motorneurons. These data highlight the utility of comparative transcriptomes for identifying transcription factor targets and understanding gene regulatory networks.

  View details for DOI 10.1534/g3.120.401515

  View details for PubMedID 32601060

  View details for PubMedCentralID PMC7466980