期刊
AUTOPHAGY
卷 12, 期 3, 页码 472-483出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2015.1136769
关键词
ATP13A2; GBA, lysosome; nanoparticles; neurodegeneration; Parkinson disease; XMEA
类别
资金
- Marie Curie Reintegration Grant from European Commission and PEPS-Idex [FP7-PEOPLE-2009-ERG256303, 1024R-3219]
- Fondation pour la Recherche Medicale
- Fondation de France Agence Nationale de la Recherche [ANR-12-BSV4-0001-01]
- LABEX BRAIN [ANR-10-LABX-43]
- MESR fellowship
- France Parkinson Foundation
- Conseil Regional d'Aquitaine (Chaire d'Accueil grant)
- Conseil Regional d'Aquitaine
Lysosomal impairment causes lysosomal storage disorders (LSD) and is involved in pathogenesis of neurodegenerative diseases, notably Parkinson disease (PD). Strategies enhancing or restoring lysosomal-mediated degradation thus appear as tantalizing disease-modifying therapeutics. Here we demonstrate that poly(DL-lactide-co-glycolide) (PLGA) acidic nanoparticles (aNP) restore impaired lysosomal function in a series of toxin and genetic cellular models of PD, i.e. ATP13A2-mutant or depleted cells or glucocerebrosidase (GBA)-mutant cells, as well as in a genetic model of lysosomal-related myopathy. We show that PLGA-aNP are transported to the lysosome within 24 h, lower lysosomal pH and rescue chloroquine (CQ)-induced toxicity. Re-acidification of defective lysosomes following PLGA-aNP treatment restores lysosomal function in different pathological contexts. Finally, our results show that PLGA-aNP may be detected after intracerebral injection in neurons and attenuate PD-related neurodegeneration in vivo by mechanisms involving a rescue of compromised lysosomes.
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