Way of Supporting Lysosomes Seen to Protect Nerve Cells in Early Study
Injecting acidic nanoparticles into mice in a model of Parkinson’s disease protected against nerve cell loss and restored the ability of lysosomes, cell compartments responsible for breaking down excess or damaged proteins, to work as they should, a research team reported.
“Our results support lysosomal re-acidification as a disease-modifying strategy for the treatment of [Parkinson’s],” the scientists wrote.
The study, “Acidic nanoparticles protect against α-synuclein-induced neurodegeneration through the restoration of lysosomal function,” was published in Aging Cell.
Parkinson’s is characterized by the toxic accumulation of misfolded alpha-synuclein in nerve cells. Lysosomes have been implicated in this process, where they are thought to be unable to clear such protein buildup.
Lysosomes normally act in a highly acidic environment, or one with a low pH. Problems in lysosomal function are often associated with compromised acidification, meaning that poorer acidification (increased pH) may lead to lysosomal dysfunction. This highlights the possibility of re-acidifying lysosomes as a way of treating Parkinson’s.
Nanoparticles are often used in research to package drugs for delivery in animal models. By their nature, a type called PLGA nanoparticles are highly acidic and readily taken up by nerve cells once administered.
A research team in France wondered if these nanoparticles could be used to re-acidify lysosomes, restoring their ability to degrade alpha-synuclein.
The scientists began by working with neurons, or nerve cells, in lab cell cultures that expressed excessive amounts of alpha-synuclein. As expected, lysosome acidification in the cells was compromised.
These cells were then treated with acidic nanoparticles (aNPs) or with non-acidic nanoparticles (NPs) as a control cell group.
Results showed that the aNPs were successfully taken up into the cells within 24 hours and delivered to the lysosomes. aNPs successfully restored lysosome acidification, whereas NPs did not.
Levels of lysosomal membrane permeabilization, a distinctive feature that indicates lysosomal dysfunction, was triggered by the over-expression of alpha-synuclein. This feature was reversed by aNP treatment, again supporting the ability of aNPs to restore function to lysosomes.
Notably, alpha-synuclein levels fell markedly — by about 50% — in aNP-treated cells, “indicating that the degradation process inside the lysosome is rescued,” the researchers wrote.
To clear old or damaged proteins, lysosomes pair with the “autophagosome” — a structure within cells that allows for the degradation of unwanted cellular components — in what is called the autophagy-lysosomal pathway. Markers of this pathway rose with aNP treatment, indicating that the re-acidification of lysosomes by acidic nanoparticles restores the autophagy-lysosomal pathway to enable alpha-synuclein clearance.
Researchers next used a mouse model of Parkinson’s disease, injecting acidic nanoparticles directly into their brain. They noted that the aNPs were readily taken up by the animals’ neurons and traveled to the lysosome, where they worked in ways similar to that seen in the cell cultures.
Four months after injection with acidic nanoparticles, their use was seen to lessen the loss of dopaminergic neurons, the nerve cells predominately affected in Parkinson’s. While a 50% loss is typically observed in this particular disease model, dopaminergic neuron loss was 20% in treated animals.
aNP treatment also lowered toxic alpha-synuclein levels to near normal, re-established an acidic pH to lysosomes, and reduced the levels of lysosomal membrane permeabilization.
“These results suggest a dramatic reduction in [alpha-synuclein]-induced neurodegeneration and pathology through aNPs administration,” the researchers wrote.
Findings in treated mice, like those of the cell cultures, suggest that aNPs’ ability to restore lysosome function aided in clearing the toxic alpha-synuclein protein and protected the mice against neurodegeneration, the researchers wrote.
“In the context of neurodegenerative diseases associated with protein aggregation, such as PD [Parkinson’s disease], Alzheimer’s disease, or amyotrophic lateral sclerosis, lysosomes are critical organelles,” they wrote.
“Thus, treatments aimed at improving lysosomal function, such as the method we present here, might prove useful for proteinopathies [diseases involving toxic protein accumulation],” the scientists concluded.