Parkin absence accelerates microtubule aging in dopaminergic neurons

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.

Amadeo, AlidaUniversity of Milan (författare)
Calogero, Alessandra MariaUniversity of Milan (författare)
Casagrande, Francesca Vittoria MarialuisaUniversity of Milan (författare)
De Gregorio, CarmelitaUniversity of Milan (författare)
Gioria, MariarosaUniversity of Milan (författare)
Kuzumaki, NaokoKeio University (författare)
Costa, IlariaUniversity of Milan (författare)
Sassone, JennyVita-Salute San Raffaele University (författare)
Ciammola, AndreaIstituto Auxologico Italiano (författare)
Hattori, NobutakaJuntendo University (författare)
Okano, HideyukiKeio University (författare)
Goldwurm, StefanoIstituti Clinici Di Perfezionamento Hospital , Milan (författare)
Roybon, LaurentLund University,Lunds universitet,Stamcellslaboratoriet för sjukdomsmodellering i det centrala nervsystemet,Forskargrupper vid Lunds universitet,IPSC Laboratory for CNS Disease Modeling,Lund University Research Groups(Swepub:lu)mphy-lra (författare)
Pezzoli, GianniIstituti Clinici Di Perfezionamento Hospital , Milan (författare)
Cappelletti, GraziellaUniversity of Milan (författare)
University of MilanKeio University (creator_code:org_t)

Av författaren/redakt...: Cartelli, Daniel ...; Amadeo, Alida; Calogero, Alessa ...; Casagrande, Fran ...; De Gregorio, Car ...; Gioria, Mariaros ...; visa fler...; Kuzumaki, Naoko; Costa, Ilaria; Sassone, Jenny; Ciammola, Andrea; Hattori, Nobutak ...; Okano, Hideyuki; Goldwurm, Stefan ...; Roybon, Laurent; Pezzoli, Gianni; Cappelletti, Gra ...; visa färre...

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