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REVIEW article
Front. Cell Dev. Biol.
Sec. Membrane Traffic and Organelle Dynamics
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1538377
This article is part of the Research TopicAutophagy Beyond Degradation: Unraveling the Secretory Function of the Endo-lysosomal SystemView all 5 articles
Small HSPs at the crossroad between protein aggregation, autophagy and unconventional secretion: clinical implications and potential therapeutic opportunities in the context of neurodegenerative diseases
Provisionally accepted
Raffaella Bonavita1
Fulvia Vitale1
Luigi Vittorio Verdicchio1
Sarah Williams2
Maria Gabriella Caporaso1
Angeleen Fleming2
Maurizio Renna1,2*- 1University of Naples Federico II, Naples, Italy
- 2University of Cambridge, Cambridge, England, United Kingdom
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Neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's and Huntington's diseases as well as ataxias and fronto-temporal disorders are all characterized by the progressive accumulation of protein aggregates (amyloids) into inclusions bodies. In addition, recent experimental evidence is challenging the conventional view of the disease by revealing the ability of some of these disease-relevant proteins to be transferred between cells by means of extracellular vesicles (EVs), allowing the mutant protein to seed oligomers involving both the mutant and wild type forms of the protein. Abnormal secretion and levels of EVs are closely related to the pathogenesis of neurodegenerative diseases and contribute to disease progression. Numerous studies have proposed EVs as therapeutic targets or biomarkers for neurodegenerative diseases. In this review, we summarize and discuss the role of small heat shock proteins (sHSPs) and autophagy in cellular quality control and turn-over of the major aggregation-prone proteins associated to neurodegenerative disorders. We also highlight the advanced research progress on mechanisms regulating unconventional secretion, secretory autophagy and EVs biogenesis and their contribution in the pathological processes underlining these diseases. Finally, we outline the latest research on the roles of EVs in neurodegenerative diseases and their potential diagnostic and therapeutic significance for the treatment of these clinically relevant conditions.
Keywords: small heat shock proteins, protein misfolding, protein oligomerization and aggregation, Autophagy, Unconventional protein secretion, Extracellular vesicles and exosomes, Neurodegenerative Diseases
Received: 02 Dec 2024; Accepted: 11 Apr 2025.
Copyright: © 2025 Bonavita, Vitale, Verdicchio, Williams, Caporaso, Fleming and Renna. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Maurizio Renna, University of Naples Federico II, Naples, Italy
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.