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Project details

ENU Team Leader: Dr Cristina Meregalli (PI PROJECT)

Other ENU members involved: Dr. Alessio Malacrida, Dr. Gabriella Nicolini, Dr. Olga Tarasiuk and in vivo group

Coordinator: Dr Cristina Meregalli

Other Participants: Universiity of Columbia, University of Michigan, Università degli Studi del PIEMONTE ORIENTALE “Amedeo Avogadro”-Vercelli, Univesity of Turin

Total Contribution: 230.900 €

Project Duration in months: 36 months (+ extension: 12 months)

Start Date: 1 novembre 2020

End Date: 1 novembre 2024

Project webpage: http://www.mitotubproject.org

 

This work is supported by Fondazione Cariplo, Grant # 2019-1482

Abstract

The proteasomal system is involved in the turnover of damaged proteins and it is responsible for the degradation of damaged proteins. Because of its role in oncogenesis, the inhibition of the proteasome system is a promising therapeutic approach for neoplastic treatment. The accumulation and deleterious effects of toxic proteins are frequently induced by exposure to chemotherapeutic drugs. Nevertheless, 20S proteasome inhibitors, such as bortezomib and carfilzomib have been approved by the U.S. Food and Drug Administration for the treatment of multiple myeloma (MM) and some other liquid tumours. Although the survival of MM patients has been improved by the introduction of both drugs-based therapies, these clinical 20S proteasome inhibitors have several limitations, including chemotherapy induced peripheral neurotoxicity (CIPN). Since that correct mitochondrial trafficking and anchoring is critical for neurons to meet energy requirements, the inhibition of microtubule (MT)-based fast axonal transport may be a significant contributor to neurotoxicity induced by MT-targeting drugs. In particular, altered mitochondrial trafficking and membrane depolarization in dorsal root ganglia (DRG) are likely contributors to CIPN progression. Moreover, it was reported that increased neuronal calcium alters mitochondrial axon transport and that TRPV4 and/or TRPA1 activation and subsequential Ca2+ influx, results in more stationary mitochondria. In addition, mitochondrial trafficking along the DRG axon is regulated by mechanisms that are influenced by tubulin isotypes, post translational modification (PTMs), motor protein and microtubule associated proteins (MAPs). Despite the great advances in dissecting the molecular mechanisms underlying CIPN, much is still unknown and improving our knowledge would provide an invaluable step toward our understanding of the disease and the development of new diagnostic and therapeutic tools. Since the alterations of cytoskeleton and mitochondrial dysfunction have been linked to CIPN, we compared these targets after BTZ and CFZ treatments by in vitro and in vivo studies.

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Understanding the role of tubulin post-translational modification and mitochondrial impairment in bortezomib-induced peripheral neurotoxicity