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1. Research Background:

The accumulation of pathological protein aggregates is a key feature observed in various age-related neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Intracellular proteins such as alpha-synuclein (α-syn) and tau, which usually play vital roles in regulating neuronal function, can undergo abnormal aggregation, thereby disrupting cellular processes. This disruption ultimately leads to neuronal dysfunction and contributes to the development of PD and AD, respectively. Crucially, both α-syn and tau aggregates exhibit "prion-like" characteristics, signifying their capacity to spread from one cell to another. These abnormal protein aggregates induce the misfolding of native proteins in neighboring neurons, leading to the propagation of neuronal damage and subsequent neurodegeneration across interconnected brain regions.

Microglia, the brain's resident innate immune cells, respond to abnormal protein aggregations by the induction of neuroinflammatory processes and the phagocytic clearance machinery^1,2. The latter, however, is impeded by inflammatory conditions, diminishing the efficiency of aggregate clearance^1,3. This inefficiency contributes to the accumulation of harmful aggregates, exacerbating the neuronal damage observed in neurodegenerative diseases.

The primary research objective of our group is to understand how microglia react to abnormal protein aggregates and discern the factors that influence their activity. Through this understanding, we aim to pinpoint potential therapeutic strategies directed at regulating microglial function and alleviating the progression of neurodegenerative diseases.

2. Research questions addresses by the group:

The mechanisms contributing to brain ageing and neurodegenerative diseases are largely unknown but may imply the induction of a feedback loop of multiple interacting cellular and molecular events leading to less efficient communication between brain cells. In keeping with this, we have recently uncovered a mechanism wherein microglia form tunneling nanotubes (TNTs), cellular protrusions connecting distant cells, to neurons and microglia suffering from the intracellular accumulation of abnormal protein aggregates⁴. This mechanism aims to rescue burdened cells from their functional impairment and to improve cell survival. However, breakdown of this process and failure in the formation of microglial TNTs to neighboring cells, e.g., due to brain ageing or the presence of inflammatory events, may aggravate pathology leading to excessive neuronal dysfunction and cell death.

The overall goal of this research group is to understand the mechanisms by which microglia control brain homeostasis through the formation of TNTs and to define their deviations during normal ageing and age-related diseases. In this way, we aim to shed light on the cellular and molecular changes in microglia that occur during ageing to circumvent the factors that contribute to neurodegenerative diseases, to endorse healthy ageing. With this, this working group will investigate a novel, so far not considered role of microglia in brain homeostasis, ageing, and the development of age-related neurodegenerative diseases.

3. Possible projects:

The primary goal of our group is to understand the mechanisms within microglia that regulate brain homeostasis and the deviations observed during aging, neurodegenerative conditions, and other brain disorders. Our research places a significant emphasis on uncovering the fundamental principles governing the interactions between microglia and neurons. Understanding these interactions is pivotal as they play a crucial role not only in normal aging but also in the progression of neurodegenerative diseases. We hope that this work will shed light on the role of microglia and re-define their functions during both normal aging and neurodegenerative processes.

Our preliminary work has raised numerous questions that we will endeavor to answer in the future. Therefore, the specific content of the PhD project can be tailored to match the candidate's interests and skills.

4. Applied Methods and model organisms:

This group employs cutting-edge molecular, biochemical, and cell biological methods, along with live cell imaging, super-resolution laser scanning techniques, and flow cytometry. Our research utilizes transgenic mouse models, primary neuron and microglia cultures, as well as human iPSC-derived neurons and microglia, to serve as model systems.

5. Desirable skills and qualifications:

We are looking for a motivated and passionate person with excellent basic knowledge in molecular and cell biology. The person should be enthusiastic about joining and actively contributing to the formation of a new and growing team. While prior experience in working with cell cultures and in neuroimmunology is a plus, it’s not a strict requirement.

6. References:

1. Scheiblich, H. et al. Microglial NLRP3 Inflammasome Activation upon TLR2 and TLR5 Ligation by Distinct α-Synuclein Assemblies. J.I. 207, 2143–2154 (2021).
2. Ising, C. et al. NLRP3 inflammasome activation drives tau pathology. Nature 575, 669–673 (2019).
3. Friker, L. L. et al. β-amyloid clustering around ASC fibrils boosts its toxicity in microglia. Cell reports 30, 3743–3754 (2020).
4. Scheiblich, H. et al. Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes. Cell 184, 5089-5106.e21 (2021).