Study identifies the role of lysosomes in the spread of Parkinson’s disease

In the past few decades, neurodegenerative diseases have turned into one of the top 10 worldwide causes of death. Scientists across the globe have been striving hard to gain insights into the pathogenesis of neurodegenerative diseases, which is crucial to develop effective treatments against these incurable diseases.

Neurodegenerative disease

Neurodegenerative Disease. Image Credit: Illustration Forest/Shutterstock.com

But researchers still lack the knowledge of the fundamental molecular mechanisms behind the pathogenesis of neurodegenerative diseases. A group of scientists identified the implication of lysosomes in the proliferation of Parkinson’s disease.

A common trait shared by various neurodegenerative diseases (NDs) is the accumulation of misfolded protein aggregates in impacted brain regions. Increasing evidence in cellular and animal models emphasizes the ability of different misfolded proteins to be transmitted and to trigger the accumulation of their endogenous counterparts, a process called “seeding.”

Parkinson’s disease is the second most common ND and presents with the accumulation of misfolded α-synuclein (α-syn) proteins in fibrillar aggregates inside neurons. Those accumulations are called Lewy bodies.

α-syn fibrils spreads through TNTs inside lysosomes

In 2016, a research team from the Institut Pasteur (Paris) and the French National Centre for Scientific Research (in French: CNRS, Centre national de la recherche scientifique) showed that α-syn fibrils diffuse from donor to acceptor cells through tunneling nanotubes (TNTs). The team also identified that these fibrils are transmitted through TNTs within lysosomes.

TNTs are actin-based membrane channels allowing the transfer of several cellular components including organelles between distant cells. Lysosomes are organelles normally deputed to the degradation and recycling of toxic/damaged cell material.”

Chiara Zurzolo, Head, Membrane Traffic and Pathogenesis Unit, Institut Pasteur

α-syn fibrils can modify lysosome shape and permeability to allow seeding and diffusion

The researchers took a cue from this original discovery and have now offered insights into how lysosomes take part in the diffusion of α-syn aggregates through TNTs.

By using super-resolution and electron microscopy, we found that α-syn fibrils affect the morphology of lysosomes and impair their function in neuronal cells. We demonstrated for the first time that α-syn fibrils induce the peripheral redistribution of the lysosomes thus increasing the efficiency of α-syn fibrils’ transfer to neighbouring cells.”

Chiara Zurzolo, Head, Membrane Traffic and Pathogenesis Unit, Institut Pasteur

The researchers also demonstrated that α-syn fibrils can permeabilize the lysosomal membrane, weakening the degradative function of lysosomes and enabling the seeding of soluble α-syn, which takes place predominantly in those lysosomes. By weakening lysosomal function, α-syn fibrils thus inhibit their own degradation in lysosomes, which instead turn into a hub for the spread of the pathology.

This breakthrough has helped elucidate the mechanism by which α-syn fibrils diffuse through TNTs while also unraveling the vital role of lysosomes, working like a Trojan horse for both seeding and spread of disease pathology. This information can be used to develop innovative therapies to target these incurable diseases.

Source:
Journal reference:

Senol, A. D., et al. (2021) α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes. PLOS Biology. doi.org/10.1371/journal.pbio.3001287.

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