Transfer of Damaged Lysosomes in the Spread of α-synuclein Pathology in the Aging Brain

Parkinson's disease is the best known of the synucleinopathies, age-related neurodegenerative conditions characterized by the damaging aggregation of misfolded α-synuclein. This is one of only a few proteins in the body that can misfold in ways that encourage other molecules of the same protein to also misfold, creating a contagion that can slowly spread from cell to cell, and aggregate into toxic structures that disrupt cell function and kill cells.

Today's research materials examine some of the details of the spread of misfolded α-synuclein. This is an important topic for the same reasons that metastasis of cancer is an important topic. Finding ways to prevent the spread to neighboring tissue would remove the worse aspects of both cancer and synucleinopathies, restricting them to localized harm. This requires a comprehensive exploration of the biochemistry involved, as a priori it is hard to say which of the presently unknown or poorly understood details will turn out to be useful.

It has become clear in recent years that mammalian cells can and do exchange component parts with one another. There is considerable evidence for the transfer of mitochondria, for example. Cells with functional mitochondria have been observed attempting to rescue cells with damaged mitochondria, extending structures called tunneling nanotubes that link two cells together, and passing mitochondria through that connection. Here, researchers observe cells doing this in order to transfer lysosomes, which act as recycling units in cells, responsible for breaking down damaged and unwanted molecules. The misfolding of α-synuclein hijacks this process in a way that favors transmission of misfolded proteins between cells, carried within damaged lysosomes.

Parkinson's disease: how lysosomes become a hub for the propagation of the pathology

The accumulation of misfolded protein aggregates in affected brain regions is a common hallmark shared by several neurodegenerative diseases (NDs). Mounting evidence in cellular and in animal models highlights the capability of different misfolded proteins to be transmitted and to induce the aggregation of their endogenous counterparts, this process is called "seeding". In Parkinson's disease, the second most common ND, misfolded α-synuclein (α-syn) proteins accumulate in fibrillar aggregates within neurons. Those accumulations are named Lewy bodies.

In 2016, a team of researchers demonstrated that α- syn fibrils spread from donor to acceptor cells through tunneling nanotubes (TNTs). They also found out that these fibrils are transferred through TNTs inside lysosomes. Following this original discovery, researchers now shed some light on how lysosomes participate in the spreading 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."

They also showed that α-syn fibrils can permeabilize the lysosomal membrane, impairing the degradative function of lysosomes and allowing the seeding of soluble α-syn, which occurs mainly in those lysosomes. Thus, by impairing lysosomal function α-syn fibrils block their own degradation in lysosomes, that instead become a hub for the propagation of the pathology.

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

The accumulation of α-synuclein (α-syn) aggregates in specific brain regions is a hallmark of synucleinopathies including Parkinson disease (PD). α-Syn aggregates propagate in a "prion-like" manner and can be transferred inside lysosomes to recipient cells through tunneling nanotubes (TNTs). However, how lysosomes participate in the spreading of α-syn aggregates is unclear. Here, by using super-resolution (SR) and electron microscopy (EM), we find that α-syn fibrils affect the morphology of lysosomes and impair their function in neuronal cells. In addition, we demonstrate that α-syn fibrils induce peripheral redistribution of lysosomes, likely mediated by transcription factor EB (TFEB), increasing the efficiency of α-syn fibrils' transfer to neighboring cells.

We also show that lysosomal membrane permeabilization (LMP) allows the seeding of soluble α-syn in cells that have taken up α-syn fibrils from the culture medium, and, more importantly, in healthy cells in coculture, following lysosome-mediated transfer of the fibrils. Moreover, we demonstrate that seeding occurs mainly at lysosomes in both donor and acceptor cells, after uptake of α-syn fibrils from the medium and following their transfer, respectively. Finally, by using a heterotypic coculture system, we determine the origin and nature of the lysosomes transferred between cells, and we show that donor cells bearing α-syn fibrils transfer damaged lysosomes to acceptor cells, while also receiving healthy lysosomes from them.

These findings thus contribute to the elucidation of the mechanism by which α-syn fibrils spread through TNTs, while also revealing the crucial role of lysosomes, working as a Trojan horse for both seeding and propagation of disease pathology.

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