Neuron-glia interactions in regulating protein aggregation in human cell models.

Project Abstract

There is one characteristic of all neurodegenerative diseases: the accumulation and aggregation of abnormal proteins in the patient’s brain. These aggregations are thought to induce neuronal cell death and brain degeneration. Therefore, it is plausible that blocking protein accumulation would have a beneficial therapeutic effect. Intriguingly, microglia, the brain’s immune cells, have been suggested to play a role in the accumulation of these proteins. We here propose to study how microglia regulate protein accumulation with the goal to provide a therapeutic opportunity to halt the disease progression. To tackle this question, we established a cell culture system consisting of human stem cell-derived neurons, astrocytes, and microglia. Expression of mutant huntingtin protein in neurons resulted in robust formation of intracellular aggregation. Surprisingly, when microglia are added to this culture, they quickly eliminate huntingtin aggregates. We have observed microglia taking up neuronal aggregates specifically without killing neurons. This remarkable effect of microglia raises many questions such as how microglia can sense the presence of aggregates inside neurons and how they can specifically extract them without affecting the integrity of the neurons. Moreover, this phenomenon could potentially be exploited for new therapeutic strategies. Here, we propose to test specific mechanisms how microglia take up aggregates and degrade it by genetically attenuating key regulatory genes. We also propose to study relevant molecules that are present on the surface of neurons which participate in microglial recognition of aggregates. Finally, we will augment the function of such key regulators and see whether it can accelerate the elimination of aggregates, which potentially provide an important new opportunity to interfere with the disease progression. Since protein accumulation in the brain is a common feature of all neurodegenerative disease, like Alzheimer’s disease or Parkinson’s disease, similar principles may very well be relevant for the many other protein aggregation diseases.