Sharing is caring - Microglia care for neurons through tunneling nanotubes

• Applicant: Dr. Hannah Scheiblich
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells ; Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 548919474

Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder, with a prevalence of 1% in people over 65 years old. Characteristic features include the formation of intraneuronal inclusions rich in the protein alpha-synuclein (α-syn) and progressive neuroinflammation, ultimately leading to neuronal dysfunction and degeneration. Microglia, resident immune cells in the central nervous system (CNS), respond to misfolded proteins by activating inflammatory pathways and control the deposition of α-syn by uptake and degradation of these proteins. In a study recently published in Cell, we demonstrated that microglia can redistribute aggregated α-syn among themselves to facilitate protein degradation, thereby enhancing their survival. However, it remains unclear whether microglia can also reduce α-syn levels in neurons to protect them from dysfunction and cell death. Preliminary data suggest that microglia are connected to neurons via tunneling nanotubes (TNTs) to uptake fibrillar α-syn from neurons. At the same time, microglia donate healthy mitochondria to α-syn-laden neurons to maintain neuronal health and reduce oxidative stress. These observations suggest that microglia may provide a new mechanism for protein homeostasis in Parkinson's disease and other neurodegenerative disorders. Investigating the interactions between neurons and microglia via TNTs is therefore crucial for understanding the role of microglia in neurodegenerative diseases. My goal is to understand the mechanisms by which microglia facilitate the removal of α-syn from neurons via intercellular TNTs. Which neuronal signaling molecules are necessary for recruiting microglia? How can microglia distinguish between healthy and diseased neurons and provide targeted assistance where needed? How is the formation of contacts between neurons and microglia regulated, and how is the exchange of "cargo" controlled and coordinated? Can we modulate this "cargo exchange" to support the positive effects on neuronal survival? All of these questions will be addressed with the experiments proposed in this project. Overall, this proposal suggests a novel cellular mechanism that has the potential to change our understanding of microglial function during brain homeostasis and disease progression, and to develop new therapeutic approaches for neurodegenerative brain diseases.

• DFG Programme: Research Grants