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Frataxin silencing alters microtubule stability in motor neurons: implications for Friedreich's ataxia
- Source :
- Human molecular genetics. 25(19)
- Publication Year :
- 2016
-
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.
- Subjects :
- 0301 basic medicine
Ataxia
Neurite
macromolecular substances
Microtubules
Antioxidants
03 medical and health sciences
Mice
0302 clinical medicine
Microtubule
Iron-Binding Proteins
Genetics
medicine
Neurites
Gene silencing
Animals
Humans
Gene Silencing
Cytoskeleton
Molecular Biology
Genetics (clinical)
Cells, Cultured
Motor Neurons
biology
Glutathione Disulfide
Iron-binding proteins
General Medicine
Axons
Cell biology
Oxidative Stress
030104 developmental biology
Tubulin
Friedreich Ataxia
biology.protein
Frataxin
medicine.symptom
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 14602083
- Volume :
- 25
- Issue :
- 19
- Database :
- OpenAIRE
- Journal :
- Human molecular genetics
- Accession number :
- edsair.doi.dedup.....090823aad35eea8f64f9775a3aa521ac