期刊
AGING CELL
卷 21, 期 4, 页码 -出版社
WILEY
DOI: 10.1111/acel.13584
关键词
acidic nanoparticles; alpha-synuclein; neurodegeneration; therapeutics; in vivo; lysosomal restoration; Parkinson's disease
资金
- French government in the framework of the University of Bordeaux's IdEx Investments for the Future program [GPR BRAIN_2030]
- Fondation de France [00066525]
- IDEX Emergence [OPE-2018-410]
- Spanish Ministry of Science and Innovation [IJCI-2017-32114]
- MSER fellowship (France)
- Fondation de France fellowship
- France Parkinson fellowship (France)
- Region Nouvelle-Aquitaine
- France Alzheimer [0033-00011]
- Connaitre les Syndromes Cerebelleux
- France Parkinson
- ARSEP
Researchers have discovered that acidic nanoparticles can improve neurodegeneration and restore lysosomal function in Parkinson's disease, offering a new treatment strategy for this and other age-related proteinopathies.
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 alpha-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 alpha-synuclein degradation through enhancing lysosomal activity in vitro. We further demonstrate in vivo that aNPs protect nigral dopaminergic neurons from cell death, ameliorate alpha-synuclein pathology, and restore lysosomal function in mice injected with PD patient-derived Lewy body extracts carrying toxic alpha-synuclein aggregates. Our results support lysosomal re-acidification as a disease-modifying strategy for the treatment of PD and other age-related proteinopathies.
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