Lysosomal impairment causes lysosomal storage disorders (LSD) and is involved in pathogenesis of neurodegenerative diseases, notably Parkinson disease (PD). Strategies enhancing or restoring lysosomalmediated 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.
The drug chlorhexidine has been widely utilized as a wound antiseptic and oral antimicrobial rinse. There have been numerous reports on its safety as an oral rinse, but its effects on wound healing have been contradictory. The present study utilized human fibroblasts derived from skin and oral tissues to test the effects of chlorhexidine on viability, growth, collagen gel contractions, and total protein synthesis. Cells were exposed for an hour to 0.005% and 0.002% chlorhexidine and for 30 seconds to 0.12% chlorhexidine. Our results indicate that a 0.002% concentration of the drug shows minimal cytotoxicity, but is able to suppress cell division almost completely. Collagen gel contraction, as a model of wound contraction, was also severely affected by all of the concentrations of chlorhexidine used. Total protein synthesis was suppressed by chlorhexidine in collagen gel culture. The data support the hypothesis that chlorhexidine is highly cytotoxic to cells in vitro, but various cell functions such as proliferation, collagen gel contraction, and protein synthesis are affected to different degrees by the drug.
The conformational strain diversity characterizing α-synuclein (α-syn) amyloid fibrils is thought to determine the different clinical presentations of neurodegenerative diseases underpinned by a synucleinopathy. Experimentally, various α-syn fibril polymorphs have been obtained from distinct fibrillization conditions by altering the medium constituents and were selected by amyloid monitoring using the probe thioflavin T (ThT). We report that, concurrent with classical ThT-positive products, fibrillization in saline also gives rise to polymorphs invisible to ThT (τ−). The generation of τ− fibril polymorphs is stochastic and can skew the apparent fibrillization kinetics revealed by ThT. Their emergence has thus been ignored so far or mistaken for fibrillization inhibitions/failures. They present a yet undescribed atomic organization and show an exacerbated propensity toward self-replication in cortical neurons, and in living mice, their injection into the substantia nigra pars compacta triggers a synucleinopathy that spreads toward the dorsal striatum, the nucleus accumbens, and the insular cortex.
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