Jonathan Daniel, France
Université de Bordeaux, Institut des Sciences Moléculaires CNRS UMR 5255Author Of 1 Presentation
ACIDIC NANOPARTICLES PROTECT AGAINST ALPHA-SYNUCLEIN-INDUCED NEURODEGENERATION THROUGH RESTORATION OF LYSOSOMAL ACTIVITY
Abstract
Aims
Parkinson disease is a neurodegenerative disease characterized by accumulation of alpha-synuclein protein enclaved in neuronal intracytoplasmic inclusions called Lewy Bodies. Genetic and neuropathological evidences indicate an alteration of the autophagy-lysosomal pathway at different levels. A likely link between these data relates to a lysosomal impairment, making it a point of particular vulnerability. To restore the autophagy-lysosomal pathway function, we chose to target the lysosomal compartment using acidic nanoparticles aiming to reestablish the appropriate and functional lysosomal pH in a PD mouse model.
Methods
We produced acidic nanoparticles made of biocompatible poly(D,L-lactide-co-glycolide) polymers, previously shown to be efficient to target lysosomal compartment and reestablish proper lysosomal pH in vitro. To test this hypothesis, we used the Lewy body mouse model of PD which consist of mice receiving human derived Lewy body containing fractions into the substantia nigra. We then injected acidic nanoparticles or non-acidic nanoparticles in the substantia nigra of Lewy body-injected or control mice.
Results
Four months post-injection, we evaluated the extent of the nigrostriatal lesions and demonstrated an attenuation of dopaminergic neurodegeneration in these animals, both at the level of nigral dopaminergic neuron cell bodies and striatal dopaminergic terminals and we showed decreased levels of total, proteinase K resistant and S129 phosphorylated alpha synuclein in the substantia nigra of acidic nanoparticles and Lewy body injected mice. In addition, we show that acidic nanoparticles increase alpha synuclein degradation through enhancing lysosomal activity.
Conclusions
In conclusion, our results support lysosomal reacidification as a disease-modifying strategy for the treatment of Parkinson disease and other synucleinopathies.