Molecular network; Molecular neuroscience; Cellular neuroscience

DNA binding and phosphorylation protect FOXP2, a transcription factor with the longest polyQ track in the proteome, from aggregation during interphase and mitosis. Harnessing these native solubility-p...

Spinal bulbar muscular atrophy (SBMA) is caused by a polyglutamine expansion (pQe) in the N-terminal transactivation domain of the human androgen receptor (AR-NTD), resulting in a combination of toxi...

Polyglutamine (polyQ) diseases, including Huntington’s disease and several spinocerebellar ataxias, are caused by abnormally expanded CAG nucleotide repeats, which encode aggregation-prone polyQ tract...

DNA binding and phosphorylation protect FOXP2, a transcription factor with the longest polyQ track in the proteome, from aggregation during interphase and mitosis. Harnessing these native solubility-p...

DNA binding and phosphorylation protect FOXP2, a transcription factor with the longest polyQ track in the proteome, from aggregation during interphase and mitosis. Harnessing these native solubility-p...

DNA binding and phosphorylation protect FOXP2, a transcription factor with the longest polyQ track in the proteome, from aggregation during interphase and mitosis. Harnessing these native solubility-promoting mechanisms utilized by FOXP2 diminishes aggregation and amyloid formation by the pathological form of Huntingtin polyQ.

An integrated structural biology approach encompassing solid-state NMR and molecular dynamics simulations was implemented to obtain an atomic view of the ordered polyglutamine core and fuzzy coat of t...

An integrated structural biology approach encompassing solid-state NMR and molecular dynamics simulations was implemented to obtain an atomic view of the ordered polyglutamine core and fuzzy coat of t...

Weng et al. investigate the function of polyglutamine (polyQ) in Runx2, demonstrating that the deletion of the polyQ repeat disrupts the interaction with KPNA3. This impairs the steric blocking effects of KPNA3 on Runx2 condensation. They revealed the unique role of polyQ repeat in modulating the liquid-like state of Runx2.

Read the full paper: Polyglutamine homorepeat regulates Runx2 condensation and cellular localization in a KPNA3-dependent manner

This comprehensive review by Villavicencio Gonzalez and Zoghbi integrates established and emerging insights into the pathogenic mechanisms of polyglutamine

Read the full paper: The Hsp40 co-chaperone DNAJC7 regulates polyglutamine aggregation and exhibits context-dependent effects on polyglycine aggregation

Huntington's disease is a severe neurodegenerative condition arising from an abnormal CAG repeat expansion in the HTT gene, which leads to the production of a mutant Huntingtin protein carrying an extended polyglutamine stretch. Although the field has largely centred on the toxic effects gained by this mutant protein, growing evidence points to the loss of normal wild-type Huntingtin function as an additional contributor to disease progression. Despite this, the cell-intrinsic roles of wild-type Huntingtin in neuronal biology remain poorly defined, in part because disentangling its specific contributions from broader network-level effects has proven technically challenging. To address this knowledge gap, we took advantage of the Drosophila huntingtin homolog (htt) and selectively manipulated its expression in the small lateral ventral neurons (sLNvs), a discrete cluster of just eight circadian pacemaker neurons that govern behavioral rhythmicity and sleep. Through targeted genetic knock-down, we show that reducing htt levels in sLNvs weakens the robustness of free-running circadian rhythms and substantially increases sleep in female flies. These behavioral changes are not rooted in developmental abnormalities, as restricting htt knock-down to adult flies reproduces the sleep phenotype across both beam-crossing and video-based locomotion assays. At the cellular level, htt loss disrupts dense core vesicle trafficking along sLNv axons, altering the fraction of motile vesicles and their velocity, and abolishing the time-of-day-dependent fluctuations in vesicle dynamics observed in these neurons. Complementary electrophysiological recordings using whole-cell patch-clamp further reveal that htt knock-down lowers action potential firing rates without perturbing resting membrane potential. Together, these results identify huntingtin as a cell-autonomous regulator of neuropeptide trafficking, neuronal excitability and circadian output. Beyond advancing our understanding of wild-type huntingtin physiology, this work carries direct relevance for HD therapeutic strategies, particularly those involving huntingtin-lowering approaches, by highlighting functions that may be unintentionally compromised. ### Competing Interest Statement The authors have declared no competing interest.

An integrated structural biology approach encompassing solid-state NMR and molecular dynamics simulations was implemented to obtain an atomic view of the ordered polyglutamine core and fuzzy coat of t...