Therapeutic potential of Hsp70 in ALS and other proteinopathies: from molecular mechanisms to gene therapy (review)
Background: Disruption of cellular proteostasis and aggregation of pathological proteins are central components in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Existing treatment approaches are aimed solely at alleviating symptoms, creating an urgent need for approaches that restore protein homeostasis. The aim of the study:To analyze in detail the neuroprotective potential of a key component of the chaperone network – the 70 kDa heat shock protein (Hsp70) – with a special focus on its mechanisms of action in amyotrophic lateral sclerosis, whose pathogenesis is centrally characterized by the aggregation of the RNA-binding proteins TDP-43 and FUS. A further objective is to evaluate the possibilities for the targeted delivery of Hsp70 to the central nervous system. Materials and methods: We conducted an analysis of current scientific publications focusing on the molecular mechanisms of chaperone-mediated neuroprotection and the role of Hsp70 in regulating proteostasis. We also examined existing therapeutic strategies: pharmacological protein induction and the use of exogenous recombinant protein and the limitations of their clinical application. Results: Three interrelated levels of neuroprotection mediated by Hsp70 were examined: prevention of primary aggregation, including through modulation of phase separation; the limited potential for disaggregation of pre-formed aggregates ("entropic pulling"); and the direction of substrates towards the ubiquitin-proteasome and autophagic degradation systems. It was emphasized that the effectiveness of Hsp70 is mediated by a complex network of interactions with Hsp90, various co-chaperones, nucleotide exchange factors, and adapter proteins (e.g. BAG3, CHIP). The fundamental limitations of existing approaches, related to delivery and context-dependent activity of Hsp70, were analyzed. The development of gene therapy strategies for treating amyotrophic lateral sclerosis based on adeno-associated viruses was substantiated, enabling targeted, long-term, and controlled expression of Hsp70 in affected neurons. Conclusion: This review summarizes current molecular data on the role of Hsp70 in neurodegeneration, analyzing translational perspectives and proposing this chaperone or its domains as a multifunctional tool in the development of disease-modifying therapy for ALS and certain other neurodegenerative diseases
Bronovitsky EV, Chaprov KD, Funikov SY, et al. Therapeutic potential of Hsp70 in ALS and other proteinopathies: from molecular mechanisms to gene therapy (review). Research Results in Biomedicine. 2026;12(2):230-268. Russian. DOI: 10.18413/2658-6533-2026-12-2-0-4
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