French Study Shows That Lysosomes Act as Trojan Horses in Parkinson’s Disease

Parkinson’s disease (PD) affects nearly one million people in the US. It is the second most common neurodegenerative pathology, with highly disabling symptoms. Its main manifestations are bradykinesia (slow movement), postural instability, muscle rigidity, and tremor at rest. French researchers have shown that lysosomes, known for being the cell recycling center, are involved in the replication of the protein responsible for this disease.

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Lewy Body

Lewy body. Image Courtesy of Dr. Andreas Becker

Parkinson’s disease is a slowly progressive chronic disease with four stages, and although its mechanisms are increasingly understood, its causes are still not clear. The symptoms of Parkinson’s disease have been thought to be caused by the degeneration of certain dopaminergic neurons located in the substantia nigra of the brain.

Pathophysiological mechanisms of Parkinson’s disease

Many biological processes are involved, but a protein that normally plays a role in synaptic transmission, the protein α-synuclein (α-syn), can, as a result of misfolding, behave like a prion and form fibrillar aggregates (Lewy bodies) within neurons. By deforming and destroying neurons, these aggregates would cause a dopamine deficit and a change in the neural messages involved in the movement.

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In 2016, using highly sophisticated imaging techniques, researchers at the Pasteur Institute and the National Center for Scientific Research (CNRS) discovered tiny tubular structures that allow the exchange of ions, viruses, and organelles between cells. These actin-rich membrane protrusions, called tunneling nanotubes (TNTs), are thought to be involved in the transfer of the misfolded proteins that causes Parkinson’s disease.

The role of lysosomes in disease progression

Lysosomes are tiny cell organelles, commonly referred to as the trash bin of a cell. Using hydrolytic enzymes, they are able to degrade unwanted endogenous molecules and organelles. However, they are now also known to be involved in many other processes (plasma membrane repair, transcription, and cellular energy metabolism). Their malfunctioning, therefore, seems to scientists to be a good track to follow to explain some pathological conditions.

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A recent study published in the journal Plos Biology showed that pathogenic α-Synuclein fibrils are spread in lysosomes via TNT. Therefore, their morphology and function would be altered. Inducing redistribution of lysosomes in the periphery of the neuron, together with membrane modification, would increase the efficiency of transport of these pathogenic proteins towards neighboring cells. Consequently, these organelles would allow optimal seeding instead of their destruction.

Lysosomes thus become the cornerstone of the spread of Parkinson’s disease and act as a veritable “Trojan horse” for the spread of pathogenic proteins to other healthy cells. Their crucial role opens up the possibility of developing new therapies to limit disease progression.

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References

α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes

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