Journal article
Frataxin silencing alters microtubule stability in motor neurons: implications for Friedreich's ataxia
Human molecular genetics, v 25(19), pp 4288-4301
01 Oct 2016
PMID: 27516386
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
To elucidate the pathogenesis of axonopathy in Friedreich's Ataxia (FRDA), a neurodegenerative disease characterized by axonal retraction, we analyzed the microtubule (MT) dynamics in an in vitro frataxin-silenced neuronal model (shFxn). A typical feature of MTs is their "dynamic instability", in which they undergo phases of growth (polymerization) and shrinkage (depolymerization). MTs play a fundamental role in the physiology of neurons and every perturbation of their dynamicity is highly detrimental for neuronal functions. The aim of this study is to determine whether MTs are S-glutathionylated in shFxn and if the glutathionylation triggers MT dysfunction. We hypothesize that oxidative stress, determined by high GSSG levels, induces axonal retraction by interfering with MT dynamics. We propose a mechanism of the axonopathy in FRDA where GSSG overload and MT de-polymerization are strictly interconnected. Indeed, using a frataxin-silenced neuronal model we show a significant reduction of neurites extension, a shift of tubulin toward the unpolymerized fraction and a consistent increase of glutathione bound to the cytoskeleton. The live cell imaging approach further reveals a significant decrease in MT growth lifetime due to frataxin silencing, which is consistent with the MT destabilization. The in vitro antioxidant treatments trigger the axonal re-growth and the increase in stable MTs in shFxn, thus contributing to identify new neuronal targets of oxidation in this disease and providing a novel approach for antioxidant therapies.
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Details
- Title
- Frataxin silencing alters microtubule stability in motor neurons: implications for Friedreich's ataxia
- Creators
- Emanuela Piermarini - Unit of Muscular and Neurodegenerative DiseasesDaniele Cartelli - Department of BiosciencesAnna Pastore - Laboratoire de BiochimieGiulia Tozzi - Unit of Muscular and Neurodegenerative DiseasesClaudia Compagnucci - Unit of Muscular and Neurodegenerative DiseasesEzio Giorda - Unit of Flow CytometryJessica D'Amico - Unit of Muscular and Neurodegenerative DiseasesStefania Petrini - Department of BiosciencesEnrico Bertini - Unit of Muscular and Neurodegenerative DiseasesGraziella Cappelletti - University of MilanFiorella Piemonte - Unit of Muscular and Neurodegenerative Diseases fiorella.piemonte@opbg.net
- Publication Details
- Human molecular genetics, v 25(19), pp 4288-4301
- Publisher
- Oxford University Press
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Web of Science ID
- WOS:000395807800012
- Scopus ID
- 2-s2.0-85021852416
- Other Identifier
- 991021900032704721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Genetics & Heredity