Periodic Reporting for period 1 - UnfearHD (Unfolding the early Htt aggregates: an interdisciplinary approach for characterizing novel molecular events that impact Heat Shock Response in Huntington Disease)
Reporting period: 2023-06-01 to 2025-05-31
Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by a pathogenic expansion in the huntingtin (Htt) protein. One of the earliest cellular changes in HD is the failure of proteostasis maintenance, notably the heat shock response (HSR), which protects cells from protein misfolding. The UnfearHD project aimed to decipher how mutant Htt disrupts HSR at the very early stages of disease, using Caenorhabditis elegans as a controlled in vivo model. By leveraging inducible Htt expression and focused molecular profiling, the project intended to define early events leading to neuronal dysfunction and identify potential modifiers of disease progression. This aligns with European strategies for innovation in age‑related health research and supports building capacity for translational neurobiology in Greece
During the fellowship, I generated new C. elegans strains expressing His‑tagged, inducible Htt‑polyQ constructs (Del, 25Q and 103Q variants), enabling temporal control over mutant protein expression. I identified a narrow early‑adulthood window when the heat shock response (HSR) remains functional despite Htt induction. In parallel, I optimized a BONCAT‑based proteomics workflow to efficiently tag and detect newly synthesized proteins during early proteotoxic stress, establishing a foundation for subsequent large‑scale proteomic profiling. These results provide valuable tools for Huntington’s disease research, and the forthcoming proteomic data are expected to reveal novel pathways involved in early disease processes. Importantly, these achievements also supported my appointment as Assistant Professor in Biochemistry at AUTH
The inducible Htt-expressing nematode model and enhanced BONCAT workflow represent significant methodological advances. They provide a novel, time-resolved platform to study proteostasis dynamics in neurodegeneration models, accessible to other researchers. These tools have already been shared with research groups at IMBB‑FORTH and an external partner lab. The expected long-term impact includes enabling discovery of early biomarkers or modulators of cellular stress relevant for therapeutic research in HD and related disorders