Biology subjects

Skeens, A.

Publications and source records attributed to Skeens, A..

3 recordsLinked to original sources

bioRxiv2026

Robust learning-driven structural and functional plasticity of spines in the mature mouse cortex

Spines in the adult cortex are thought to be highly stable, and that their capacity for modest remodeling supports learning. Using a visual association task and a multilevel imaging approach in adult mice, we found a robust learning-driven increase in the complexity of spine nanostructure, as well as a rapid and persistent increase in spine formation during task acquisition that were accompanied by an overall reduction in spine size of layer 2/3 neurons in the primary visual cortex (V1). Trained animals further had an increased fraction of spines tuned to the task-relevant orientations, and the discriminability of spine responses in naive mice was predictive of their subsequent performance. Our results demonstrate that learning drives an increase in spine preferences for task-relevant information and point to reconfiguration of spine nanostructure and spine inputs as the structural drivers of these changes.

neuroscience↗

bioRxiv2024

Blocking the ability of huntingtin to bind membranes: a therapeutic strategy for Huntingtons disease

The ordered aggregation of proteins into amyloid fibrils is a hallmark of numerous neurodegenerative diseases. A common strategy in developing therapeutics for amyloid-based diseases relies on preventing or manipulating the aggregation process. However, many amyloid-forming proteins and their aggregates bind and damage organelle and cellular membranes. As such, blocking the ability of these proteins from directly interacting with membranes represents a unique therapeutic strategy. Using a mutant huntingtin (htt) protein associated with Huntingtons disease (HD) as a model system, the viability of this strategy was evaluated. Screening over 1200 compounds for their ability to block htt binding to lipid vesicles, two compounds, Ro90-7501 (Ro) and Benzamil (Ben), were identified and validated. Despite directly interacting with htt, neither compound prevented fibril formation. Molecular dynamics simulations suggested each compound has a unique mechanism of action, consistent with experimental data. Importantly, both compounds ameliorated phenotype in a C. elegans model of HD.

biophysics↗

bioRxiv2023

Oligomerization enhances huntingtin membrane activity but is suppressed by covalent crosslinking

Huntingtin disease (HD) is a neurodegenerative disease caused by expansion of a polyglutamine (polyQ) tract within the huntingtin (htt) protein, leading to aggregation into a variety of species ranging from small oligomers to large fibrils. A consensus concerning which of these aggregate states are primarily responsible for toxicity associated with mutant htt remains elusive. Htt directly binds and damages a variety of membranous surfaces within cells. Here, the ability of different aggregation states of htt to interact with and damage lipid membranes was determined. Oligomers represented the most active lipid binding species, whereas, fibril formation severely limited membrane binding. Thus, strategies to stabilize oligomers were implemented, and conformational flexibility appeared to play a key role in the oligomer/membrane interaction. In particular, stabilizing oligomers with covalent crosslinking with 1,5-difluoro-2,4-dinitrobenzene (DFDNB) effectively eliminated the ability of oligomers to bind lipid membranes and reduced their associated cellular toxicity.

biophysics↗