Acidic nanoparticles protect against α-synuclein-induced neurodegeneration through the restoration of lysosomal function

Aging Cell. 2022 Apr;21(4):e13584. doi: 10.1111/acel.13584. Epub 2022 Mar 23.


Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, associated with the accumulation of misfolded α-synuclein and lysosomal impairment, two events deemed interconnected. Protein aggregation is linked to defects in degradation systems such as the autophagy-lysosomal pathway, while lysosomal dysfunction is partly related to compromised acidification. We have recently proven that acidic nanoparticles (aNPs) can re-acidify lysosomes and ameliorate neurotoxin-mediated dopaminergic neurodegeneration in mice. However, no lysosome-targeted approach has yet been tested in synucleinopathy models in vivo. Here, we show that aNPs increase α-synuclein degradation through enhancing lysosomal activity in vitro. We further demonstrate in vivo that aNPs protect nigral dopaminergic neurons from cell death, ameliorate α-synuclein pathology, and restore lysosomal function in mice injected with PD patient-derived Lewy body extracts carrying toxic α-synuclein aggregates. Our results support lysosomal re-acidification as a disease-modifying strategy for the treatment of PD and other age-related proteinopathies.

Keywords: Parkinson's disease; acidic nanoparticles; alpha-synuclein, neurodegeneration, therapeutics; in vivo; lysosomal restoration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Lysosomes / metabolism
  • Mice
  • Nanoparticles*
  • Parkinson Disease* / metabolism
  • Substantia Nigra / metabolism
  • alpha-Synuclein / metabolism


  • alpha-Synuclein