Exposure to environmental toxins, including hydrocarbon solvents, increases the risk of developing Parkinson's disease. An emergent hypothesis considers microtubule dysfunction as one of the crucial events in triggering neuronal degeneration in Parkinson's disease. Here, we used 2,5-hexanedione (2,5-HD), the toxic metabolite of n-hexane, to analyse the early effects of toxin-induced neurodegeneration on the cytoskeleton in multiple model systems. In PC12 cells differentiated with nerve growth factor for 5 days, we found that 2,5-HD treatment affected all the cytoskeletal components. Moreover, we observed alterations in microtubule distribution and stability, in addition to the imbalance of post-translational modifications of α-tubulin. Similar defects were also found in vivo in 2,5-HD-intoxicated mice. Interestingly, we also found that 2,5-HD exposure induced significant changes in microtubule stability in human skin fibroblasts obtained from Parkinson's disease patients harbouring mutations in PRKN gene, whereas it was ineffective in healthy donor fibroblasts, suggesting that the genetic background may really make the difference in microtubule susceptibility to this environmental Parkinson's disease-related toxin. In conclusion, by showing the imbalance between dynamic and stable microtubules in hydrocarbon-induced parkinsonism, our data support the crucial role of microtubule defects in triggering neurodegeneration.
The imbalance between dynamic and stable microtubules underlies neurodegeneration induced by 2,5-hexanedione / F.V.M. Casagrande, A. Amadeo, D. Cartelli, A.M. Calogero, D. Modena, I. Costa, F. Cantele, E. Onelli, A. Moscatelli, M. Ascagni, G. Pezzoli, G. Cappelletti. - In: BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR BASIS OF DISEASE. - ISSN 0925-4439. - 1866:1(2020 Jan 01).
|Titolo:||The imbalance between dynamic and stable microtubules underlies neurodegeneration induced by 2,5-hexanedione|
AMADEO, ALIDA (Secondo)
CAPPELLETTI, GRAZIELLA (Ultimo) (Corresponding)
|Parole Chiave:||2,5-Hexanedione; Human skin fibroblasts; Microtubule dysfunction; Neurodegeneration; Parkinson's disease; Post-translational modified tubulins|
|Settore Scientifico Disciplinare:||Settore BIO/16 - Anatomia Umana|
Settore BIO/06 - Anatomia Comparata e Citologia
|Data di pubblicazione:||1-gen-2020|
|Centro di ricerca:||Centro Interdipartimentale di Eccellenza per le Malattie Neurodegenerative CEND|
|Data ahead of print / Data di stampa:||29-ott-2019|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.bbadis.2019.165581|
|Appare nelle tipologie:||01 - Articolo su periodico|