Nanoparticles restore lysosomal acidification defects: Implications for Parkinson and other lysosomal-related diseases

Abstract

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.

Toxicological Risk Assessment of Emerging Nanomaterials: Cytotoxicity, Cellular Uptake, Effects on Biogenesis and Cell Organelle Activity, Acute Toxicity and Biodistribution of Oxide Nanoparticles

“…This phenomenon can also limit the delivery of therapeutic nanoparticles to the intracellular target site. Nanoparticles depending on its physicochemical nature can alter the function of lysosome and subsequently favor the activation or the inhibition of autophagy [64][65][66]. For instance, we have observed that ZnO nanoparticles induce a loss of lysosome membrane integrity in BV2 cells at high-dose exposure (80 mg/mL) as seen by flow cytometry detection of acridine orange (Figure 2).…”

Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

“…ATP13A2 may protect against toxicity of α-syn by promoting its lysosomal clearance (Gitler et al, 2009; Usenovic et al, 2012). Loss of ATP13A2 causes impaired lysosomal acidification and reduced lysosomal proteolysis (Dehay et al, 2012b), while increased lysosomal pH is observed in fibroblasts from PD patients with ATP13A2 mutations (Bourdenx et al, 2016). …”

“…Mutations in glucocerebrosidase (GBA), which can be associated with either PD or Gaucher Disease (an LSD), also impair lysosomal function, as GBA is a lysosomal enzyme essential for processing of substrates (Mazzulli et al, 2011). Additionally lysosomal de-acidification has been observed in human fibroblasts from PD patients with GBA mutations (Bourdenx et al, 2016). …”

“…Similarly, rotenone, another environmental risk factor for PD (Betarbet et al, 2000), impairs lysosomal acidification and lysosomal activity in an NADPH oxidase-dependent manner (Pal et al, 2016). MPP + , a neurotoxin which promotes Parkinsonian symptoms, also causes de-acidification of lysosomes in cultured cells (Bourdenx et al, 2016). Together, these studies suggest that lysosomal de-acidification and dysfunction are common factors in genetic, sporadic, and toxicity-induced forms of PD/Parkinsonism.…”

Catechol Tetrahydroisoquinolines Enhance a-Synuclein Aggregation and Specify the Neurotoxicity to Dopaminergic Neurons

“…This figure was originated from Deng et al [78] with permission were exposed to Trichloroethylene (TCE), one kind of solvents, they showed the nigrostriatal degeneration, the onset of parkinsonian features, a loss of nigral dopaminergic neurons and increased nigral accumulation of α-syn [108,109]. Now, nanoparticles (NPs) have been used as new approaches for the treatment of PD [110,111]. However, in some conditions, the NPs can induce the adverse effect on the DA neurons and may accelerate the development of PD possibly through decreasing DA concentration and TH levels, increasing oxidative stress, changing mitochondrial metabolism, inhibiting cell proliferation and enhancing cell apoptosis [112][113][114].…”