title: Nanoparticles restore lysosomal acidification defects: Implications for Parkinson and other lysosomal-related diseases.
abstract: 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.
authors.affiliation: a University de Bordeaux, Institut des Maladies Neurodégénératives , UMR 5293, Bordeaux , France.|b CNRS, Institut des Maladies Neurodégénératives , UMR 5293, Bordeaux , France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bourdenx
authors.affiliation: c University de Bordeaux, Institut des Sciences Moléculaires , UMR 5255, Talence , France.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Daniel
authors.affiliation: c University de Bordeaux, Institut des Sciences Moléculaires , UMR 5255, Talence , France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Genin
authors.affiliation: a University de Bordeaux, Institut des Maladies Neurodégénératives , UMR 5293, Bordeaux , France.|b CNRS, Institut des Maladies Neurodégénératives , UMR 5293, Bordeaux , France.
authors.forename: Federico N
authors.initials: FN
authors.lastname: Soria
authors.affiliation: c University de Bordeaux, Institut des Sciences Moléculaires , UMR 5255, Talence , France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Blanchard-Desce
authors.affiliation: a University de Bordeaux, Institut des Maladies Neurodégénératives , UMR 5293, Bordeaux , France.|b CNRS, Institut des Maladies Neurodégénératives , UMR 5293, Bordeaux , France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
authors.affiliation: a University de Bordeaux, Institut des Maladies Neurodégénératives , UMR 5293, Bordeaux , France.|b CNRS, Institut des Maladies Neurodégénératives , UMR 5293, Bordeaux , France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dehay
mesh_terms: D015655:1-Methyl-4-phenylpyridinium; D000143:Acids / Q000378:metabolism*; D000468:Alkalies / Q000737:chemistry; D000818:Animals; D016923:Cell Death; D059290:Dopaminergic Neurons / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007276:Injections, Intraventricular; D019344:Lactic Acid / Q000737:chemistry; D016464:Lysosomal Storage Diseases / Q000473:pathology*; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008954:Models, Biological; D008957:Models, Genetic; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D017072:Neostriatum / Q000473:pathology; D009410:Nerve Degeneration / Q000473:pathology; D010300:Parkinson Disease / Q000473:pathology*; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer
chemical_list: D000143:Acids; D000468:Alkalies; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D015655:1-Methyl-4-phenylpyridinium
keywords: ATP13A2; GBA, lysosome; nanoparticles; Parkinson disease; XMEA; neurodegeneration