Parkin absence accelerates microtubule aging in dopaminergic neurons

Research output: Contribution to journalArticle

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.

Details

Authors
  • 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
Organisations
External organisations
  • University of Milan
  • Keio University
  • Istituto Auxologico Italiano
  • Juntendo University
  • Istituti Clinici di Perfezionamento (ICP)
  • University Vita-Salute San Raffaele
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurosciences

Keywords

  • Aging, Dopaminergic neurons, Microtubule, Parkin, Parkinson's disease, Tubulin post-translational modifications
Original languageEnglish
Pages (from-to)66-74
JournalNeurobiology of Aging
Volume61
Publication statusPublished - 2018 Jan
Publication categoryResearch
Peer-reviewedYes