Advanced Science· 2026Q1
Huntingtin Aggregate‐Responsive Autophagy Gene Circuit Mitigates Disease Pathology in R6/2 Mice
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- Q1SCImago
- 2026year
Short summary
A synthetic gene circuit (ARAA) engineered to recognize mutant huntingtin (mHTT) aggregates and activate autophagy significantly reduced mHTT burden, neuroinflammation, and motor deficits, extending lifespan in R6/2 HD mice.
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Key points
- A synthetic gene circuit (ARAA) was engineered to recognize aggregated mutant huntingtin (mHTT) and activate autophagy.
- ARAA utilizes a bacterial NarX-NarL system fused with a conformation-sensitive intrabody to detect pathological polyQ conformers.
- The circuit triggers the expression of TFEB, a master autophagy regulator.
- ARAA, delivered via CD98-targeted immunoliposomes, crossed the blood-brain barrier and reduced mHTT burden in R6/2 mice.
- Treatment improved motor function, attenuated neuroinflammation, rescued synaptic deficits, and extended lifespan in the mouse model.
AI-generated from the title and abstract; the full text is not read.
Abstract
ABSTRACT The accumulation of mutant huntingtin (mHTT) aggregates drives the pathology of Huntington's disease (HD), yet therapies capable of distinguishing toxic species from wild‐type proteins remain elusive. Here, a synthetic gene circuit, termed ARAA, was engineered to couple the preferential recognition of aggregated polyQ species to the on‐demand activation of autophagy. Utilizing a repurposed bacterial NarX–NarL system fused with a conformation‐sensitive intrabody, the circuit detects pathological polyQ conformers and triggers the transcriptional expression of the master autophagy regulator TFEB. To enable systemic application, the ARAA plasmid is encapsulated in CD98‐targeted immunoliposomes (LIP‐CD98) that facilitate efficient blood‐brain barrier crossing via receptor‐mediated transcytosis. In the R6/2 HD mouse model, ARAA treatment significantly reduces mHTT burden, attenuates neuroinflammation, and rescues synaptic deficits. This closed‐loop intervention improves motor function and extends lifespan. Together, these findings provide proof‐of‐concept evidence that aggregate‐responsive regulation of autophagy can mitigate disease‐associated phenotypes in exon 1‐based HD models.
The authors' abstract, as published at the source. Advanced Science, 2026 · DOI ↗
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Field: Cellular and Molecular Neuroscience
Cellular and Molecular NeuroscienceNeuroscience