HSF-1 Regulates Autophagy to Govern Motor Function and Facilitate Toxic Protein Clearance in a C. elegans Model of Amyotrophic Lateral Sclerosis
Hui Xu1 · Yaping Shao1 · Jun Zhang1 · Yang Ni1 · Guowang Xu2 · Cong Liu3,4 · Yi Liang5 · Weidong Le1,6
1 Key Laboratory of Liaoning Province for Research on the Pathogenic Mechanisms of Neurological Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian 116021, China
2 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
3 Interdisciplinary Research Center on Biology and Chemistry, State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
4 Shanghai Academy of Natural Sciences (SANS), Fudan University, Shanghai 200433, China
5 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430072, China
6 Neurology Program, Sir Run‑Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
Abstract
Heat shock factor-1 (HSF-1) plays a crucial role in orchestrating stress responses across diverse organisms and disease conditions. Here, we investigate how the HSF-1 signaling pathway influences the degradation of toxic proteins and neuropathological changes in the Caenorhabditis elegans model of amyotrophic lateral sclerosis (ALS). We found that overexpressing HSF-1 improves locomotor ability and increases the survival rate of ALS C. elegans. Moreover, we observed a deceleration of motor neuron degeneration, demonstrating the protective effect of HSF-1 on neurodegenerative processes. Transcriptomic analysis revealed notable changes in genes associated with autophagy and neurodegeneration, underscoring HSF-1’s critical involvement in ALS pathology. In addition, metabolomic profiling further highlighted the involvement of this pathway in metabolic reprogramming. Overall, our study underscores the critical role of the HSF-1 signaling pathway in improving survival rate, movement velocity, cellular integrity, and metabolic adaptation, providing new insights into the mechanisms underlying ALS and potential targets for therapeutic intervention.
Keywords
ALS; Autophagy; Caenorhabditis elegans; HSF-1 signaling pathway; Neuroprotection
