Parkin absence accelerates microtubule aging in dopaminergic neurons

Daniele Cartelli, Alida Amadeo, Alessandra Maria Calogero, Francesca Vittoria Marialuisa Casagrande, Carmelita De Gregorio, Mariarosa Gioria, Naoko Kuzumaki, Ilaria Costa, Jenny Sassone, Andrea Ciammola, Nobutaka Hattori, Hideyuki Okano, Stefano Goldwurm, Laurent Roybon, Gianni Pezzoli, Graziella Cappelletti

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15 Citations (Scopus)

Abstract

Loss-of-function caused by mutations in the parkin gene (PARK2) lead to early-onset familial Parkinson's disease. Recently, mechanistic studies proved the ability of parkin in regulating mitochondria homeostasis and microtubule (MT) stability. Looking at these systems during aging of PARK2 knockout mice, we found that loss of parkin induced an accelerated (over)acetylation of MT system both in dopaminergic neuron cell bodies and fibers, localized in the substantia nigra and corpus striatum, respectively. Interestingly, in PARK2 knockout mice, changes of MT stability preceded the alteration of mitochondria transport. Moreover, in-cell experiments confirmed that loss of parkin affects mitochondria mobility and showed that this defect depends on MT system as it is rescued by paclitaxel, a well-known MT-targeted agent. Furthermore, both in PC12 neuronal cells and in patients' induced pluripotent stem cell–derived midbrain neurons, we observed that parkin deficiencies cause the fragmentation of stable MTs. Therefore, we suggest that parkin acts as a regulator of MT system during neuronal aging, and we endorse the hypothesis that MT dysfunction may be crucial in the pathogenesis of Parkinson's disease.

Original languageEnglish
Pages (from-to)66-74
Number of pages9
JournalNeurobiology of Aging
Volume61
DOIs
Publication statusPublished - 2018 Jan 1

Keywords

  • Aging
  • Dopaminergic neurons
  • Microtubule
  • Parkin
  • Parkinson's disease
  • Tubulin post-translational modifications

ASJC Scopus subject areas

  • Neuroscience(all)
  • Ageing
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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  • Cite this

    Cartelli, D., Amadeo, A., Calogero, A. M., Casagrande, F. V. M., De Gregorio, C., Gioria, M., Kuzumaki, N., Costa, I., Sassone, J., Ciammola, A., Hattori, N., Okano, H., Goldwurm, S., Roybon, L., Pezzoli, G., & Cappelletti, G. (2018). Parkin absence accelerates microtubule aging in dopaminergic neurons. Neurobiology of Aging, 61, 66-74. https://doi.org/10.1016/j.neurobiolaging.2017.09.010