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

Abstract

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.

Nanotherapeutic and Stem Cell Therapeutic Strategies in Neurodegenerative Diseases: A Promising Therapeutic Approach

“… 20 , 46 Additionally, nanoparticles can also act as bioactive nanomedicines to clear abnormally aggregated proteins by modulating the autophagy-lysosomal pathway (ALP) and the ubiquitin proteasome system (UPS) pathways. 47 , 48 …”

“…20,46 Additionally, nanoparticles can also act as bioactive nanomedicines to clear abnormally aggregated proteins by modulating the autophagy-lysosomal pathway (ALP) and the ubiquitin proteasome system (UPS) pathways. 47,48 In addition, nanomaterials can also be used for imaging/contrast/tracing in neurodegenerative disease treatment. Nanomaterials including rare-earth fluorescent materials, metal nanoclusters as well as quantum dots (QDs) can be exploited as fluorescent agents for bioimaging.…”

The Zinc Ionophore Clioquinol Reduces Parkinson’s Disease Patient-Derived Brain Extracts-Induced Neurodegeneration

“…In LB-injected mice, we noticed that lysosomal function is impaired by the mislocalization of these organelles within the cell. When the lysosomes are functional, they are predominantly located around the nucleus, and their increased distance to the nucleus demonstrates their inactivity [39][40][41]. Our study showed that when LB mice were treated with ClQ, the number of lysosomes located close to the nucleus was increased compared to untreated LB-injected mice.…”

“…Figure 3B). Second, we examined whether a change in cellular localization of lysosomes could be observed, as an index of the lysosomal function [39]. Functional lysosomes are preferentially located in the perinuclear region, whereas dysfunctional lysosomes are further from the nucleus [40,41].…”

Modulating Lysosomal pH through Innovative Multimerized Succinic Acid-Based Nucleolipid Derivatives

“…4 Thus, therapeutic approaches targeting lysosomes to favor an impaired pH decrease have been proven to be a promising strategy in animal models. 5,6 Nevertheless, there was a lack of systems to achieve lysosomal acidification in therapeutics. Some acid-based molecules have shown interesting properties; in particular, poly(DL-lactide-co-glycolide) (PLGA) has been described as an efficient acidifying active ingredient 7 that releases two monomers: lactic acid and glycolic acid.…”