Biology subjects

Ammar, O.

Publications and source records attributed to Ammar, O..

2 recordsLinked to original sources

bioRxiv2026

HAP40 functions as a proteostasis regulator by controlling huntingtin interactions and its release into the extracellular space

Huntingtin-associated protein 40 (HAP40) forms a stable protein complex with huntingtin (HTT). Its cellular function and how HAP40 loss influences mutant HTT (mHTT) abundance and pathobiology are currently unclear. Here, using diverse cellular models and OMICs methods, we demonstrate that HAP40 is an obligate interaction partner of full-length HTT and through its binding controls the abundance of HTT-associated proteins, indicating that it functions as HTT interaction regulatory unit. Also, loss of HAP40 in mHTT-expressing striatal cells impairs autophagosome-lysosome flux, triggers massive transcriptional dysregulation, including the activation of the CLEAR network, demonstrating that it functions as proteostasis regulator that acts on quality control pathways. Finally, mHTT-expressing cells lacking HAP40 showed increased secretion of mHTT through the ER-to-Golgi route, indicating that striatal cells reduce intracellular mHTT-induced proteotoxicity through activation of secretory pathways. Together, these results establish HAP40 as a critical proteostasis regulator that through controlling HTT interactions maintains cellular homeostasis.

cell biology↗

bioRxiv2025

Formation of amyloid-like HTTex1 aggregates in neurons, downregulation of synaptic proteins and early mortality of Huntington's disease flies are causally linked

Amyloidogenic mutant huntingtin exon-1 (mHTTex1) protein aggregates with pathogenic polyglutamine (polyQ) tracts are the potential root cause of Huntingtons disease (HD). Here, we assessed the gain-of-function toxicity of mHTTex1 aggregation in neurons of HD transgenic flies. We show that the rate of mHTTex1 aggregation in neurons and early mortality of HD transgenic flies are correlated. We observed sequestration of key synaptic proteins into amyloid-like mHTTex1 aggregates and a concomitant decrease of their transcript levels, suggesting that progressive mHTTex1 aggregate stress in neurons leads to an impairment of synaptic function. Machine learning-based data analysis revealed that the abundance of synaptic proteins such as the vesicular monoamine transporter Vmat in the brain is predictive of fly survival. RNAi knockdown of Vmat-encoding transcripts in neurons with pathogenic amyloid-like HTTex1Q97 aggregates further shortened the lifespan of HD flies, supporting the hypothesis that mHTTex1 aggregation drives impairment of synaptic processes and pathogenesis of HD.

molecular biology↗