Nanoparticles restore lysosomal acidification defects: Implications for Parkinson and other lysosomal-related diseases

Autophagy. 2016;12(3):472-83. doi: 10.1080/15548627.2015.1136769.

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.

Keywords: ATP13A2; GBA, lysosome; nanoparticles; Parkinson disease; XMEA; neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenylpyridinium
  • Acids / metabolism*
  • Alkalies / chemistry
  • Animals
  • Cell Death
  • Dopaminergic Neurons / metabolism
  • Humans
  • Hydrogen-Ion Concentration
  • Injections, Intraventricular
  • Lactic Acid / chemistry
  • Lysosomal Storage Diseases / pathology*
  • Lysosomes / metabolism*
  • Lysosomes / ultrastructure
  • Mice
  • Models, Biological
  • Models, Genetic
  • Nanoparticles / chemistry*
  • Nanoparticles / ultrastructure
  • Neostriatum / pathology
  • Nerve Degeneration / pathology
  • Parkinson Disease / pathology*
  • Polyglycolic Acid / chemistry
  • Polylactic Acid-Polyglycolic Acid Copolymer

Substances

  • Acids
  • Alkalies
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • Lactic Acid
  • 1-Methyl-4-phenylpyridinium