(Press-News.org)
Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis (ALS) affect millions of people worldwide, yet treatments remain largely limited to symptom management. A defining feature shared by these conditions is the buildup of misfolded proteins that damage neurons over time. Cells normally rely on a protein quality-control system to prevent this damage. At the center of this system are molecular chaperones or heat shock proteins, which help proteins fold correctly or direct misfolded proteins to degradation and helps maintain proteostasis. Among them, the Hsp70 family has attracted growing attention for its ability to counteract protein aggregation, a key driver of neurodegeneration.
Recently, a research team led by Dr. Amit Mishra from the Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, India, reviewed decades of laboratory and animal research to better understand the mechanistic role and potential therapeutic value of Hsp70 chaperones in neurodegenerative diseases. This article was made available online on 12 June 2025 and was published in Volume 1, Issue 4 of the journal Brain Network Disorders on 26 December 2025.
“Our review provides a mechanistic overview of how Hsp70 chaperones interact with disease-associated proteins and mediate their clearance from the cell in neurodegenerative diseases, addressing research gaps to some extent,” says Dr. Mishra.
The review draws on studies from cell cultures, Drosophila, and mice models to show that increasing Hsp70 activity can protect neurons from toxic proteins such as amyloid β and tau in Alzheimer’s disease, α-synuclein in Parkinson’s disease, mutant huntingtin in Huntington’s disease, and superoxide dismutase 1 and TAR DNA binding protein-43 in ALS. In mice models, overexpression of Hsp70 delayed disease progression and improved survival or motor function.
Importantly, the researchers highlight that not all Hsp70 proteins behave the same way. Different isoforms (closely related versions of the protein) can have opposite effects depending on the disease and the stage at which they are activated.
In addition, they reveal how Hsp70 proteins interact with co-chaperones and cellular pathways such as autophagy and the proteasome, which together determine whether toxic proteins are cleared or persist.
While Hsp70 chaperones exert neuroprotective effects and prevent aggregation of pathological protein, inhibition of Hsp70 isoforms can be beneficial in disease conditions. For instance, direct Hsp70 modulators, HSF1 inducers, Hsp90 inhibitors, and exogenous Hsp70, have been investigated and validated in transgenic mice and Drosophila models for the treatment of neurodegenerative diseases.
Several compounds that indirectly boost Hsp70 activity (including arimoclomol) have reached human testing, especially for ALS. While early animal data were encouraging, recent clinical trials have underscored how difficult it is to translate chaperone-based therapies into consistent benefits for patients.
Degradation of mutant misfolded proteins using targeted protein degradation approach holds great potential for treatment of neurodegenerative diseases. Thus, studies on use of molecular chaperones for targeted degradation in neurodegenerative disorders can help develop a chaperone-based proteolysis therapeutic strategy.
“Our review provides comprehensive observations on Hsp70-based molecular mechanisms implicated in neurodegeneration, paving the way for development of chaperone-based therapeutic strategies. In addition, further studies exploring the effects of different Hsp70 isoforms as well as their interactions with different co-chaperones are needed to develop better therapeutic strategies against neurodegeneration,” concludes Dr. Mishra.
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Reference
DOI: 10.1016/j.bnd.2025.05.001
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