TNFRSF10B protein shows promise as therapeutic target in Parkinson’s
Suppressing this protein lessened neurodegeneration, motor dysfunction in mice
Microglia, the brain’s resident immune cells, may contribute to Parkinson’s disease by releasing tiny vesicles filled with alpha-synuclein — the protein that builds up to toxic levels in Parkinson’s — a mouse study suggests.
This release, which was associated with greater nerve cell damage and worse motor function, was found to be promoted by higher levels of a protein called TNFRSF10B. Higher levels of this protein were also found in people diagnosed with Parkinson’s and linked to more severe symptoms.
Suppressing TNFRSF10B or microglia’s ability to release the tiny vesicles lessened neurodegeneration in lab-grown mouse cells and motor dysfunction in a disease model.
“These results suggest that TNFRSF10B may be used for diagnosis [as a] biomarker and therapeutic [target] in PD [Parkinson’s],” researchers wrote.
The study, “TNFRSF10B is involved in motor dysfunction in Parkinson’s disease by regulating exosomal α-synuclein secretion from microglia,” was published in the Journal of Chemical Neuroanatomy.
Blood TNFRSF10B levels found significantly higher in people with Parkinson’s
Parkinson’s progressive neurodegeneration is thought to be driven by the toxic accumulation of alpha-synuclein clumps. These aggregates can spread from one nerve cell to another, contributing to the progression of Parkinson’s. How exactly this happens remains unclear.
Microglia are “the main immune cells in the brain, and microglial activation is involved in the initiation and progression of PD, including the release of pro-inflammatory [molecules],” the researchers wrote.
Previous studies have suggested that microglia contribute to protein clumping-associated neurodegeneration by releasing exosomes carrying such proteins. Exosomes are tiny molecule-filled vesicles that cells release to communicate with other cells.
Now, a team of researchers in China analyzed the potential molecular mechanisms underlying microglia’s release of alpha-synuclein-containing exosomes in Parkinson’s. They focused on TNFRSF10B, a protein located at the surface of cells and that the team found was involved in alpha-synuclein aggregation or in Parkinson’s.
First, the researchers looked for differences in the levels of TNFRSF10B between 22 Parkinson’s patients and 15 healthy people (controls).
Results showed that blood TNFRSF10B levels were significantly higher in people with Parkinson’s than in controls. Also, higher levels of TNFRSF10B were associated with greater Parkinson’s-associated disability, as assessed with the Hoehn and Yahr scale, and higher levels of alpha-synuclein in the blood.
Next, the researchers added alpha-synuclein fibrils, a form of toxic clumps known to promote further aggregation, to lab-grown mouse microglia and observed that TNFRSF10B levels went up.
These microglia released inflammatory molecules and exosomes that were filled with alpha-synuclein. Fibril-treated microglia were also found to significantly increase alpha-synuclein aggregation and damage in lab-grown mouse brain cells.
These effects were lessened when these microglia were treated with a compound that blocks exosome release.
“This indicates that hampering the release of [alpha-synuclein-containing exosomes] from microglia reduces the communication of [alpha-synuclein] to neurons and mediates damage to [brain] neurons,” the team wrote.
When the researchers suppressed the production of TNFRSF10B in fibril-treated microglia, the cells released fewer inflammatory molecules and alpha-synuclein-containing exosomes.
When placed in contact with lab-grown brain cells, these microglia did not damage them as much. Moreover, the nerve cells themselves did not contain as much alpha-synuclein, indicating that “inhibition of TNFRSF10B inhibits microglia-mediated [alpha-synuclein] delivery,” the researchers wrote.
Increased TNFRSF10B production in mice led to worse performance on tests
The team then treated a group of healthy mice with alpha-synuclein fibrils, which is known to promote Parkinson’s-like disease. These mice were not as good as untreated mice at coordinating muscle movements when walking on a rotating rod (rotarod). They also fell off sooner from hanging from a wire.
Mice treated with both alpha-synuclein fibrils and PLX3397, a chemical that kills nearly all microglia, performed better on the rotarod and hang wire tests than did mice treated with the fibrils only.
However, when these animals were modified to produce more TNFRSF10B, they performed worse on both tests. Moreover, “the worsening was more pronounced over time.”
In addition, PLX3397 treatment reduced alpha-synuclein deposition and death of dopamine-producing nerve cells — cells which are typically lost in people with Parkinson’s — but these effects were reversed by inducing increased TNFRSF10B production.
“Taken together, these results indicate that TNFRSF10B promotes neuronal injury and motor dysfunction by delivery of [alpha-synuclein]-containing [exosomes],” the researchers wrote, adding that tuning down TNFRSF10B could provide a potential therapeutic strategy in Parkinson’s.
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