Xenotransplantation of iPSC-derived microglia to elucidate the impact of C9orf72 hexanucleotide repeat expansion on neuroinflammation and neurodegeneration. 01/10/2023 - 30/09/2024

Abstract

A non-coding GGGGCC hexanucleotide repeat expansion (HRE) in the C9orf72 (C9) gene is the most common genetic cause of frontotemporal dementia (FTD) and associates with Amyotrophic lateral sclerosis (ALS). At present, how this mutation leads to neurodegeneration is unclear. Like other genes linked to FTD, C9 is highly expressed in microglia, suggesting that C9 mutation could lead to microglial dysfunction. This is of particular interest as altered microglial cells are known to contribute to the pathogenic mechanisms that lead to neurodegeneration in ALS and FTD patients. In this project, I will investigate how the C9 HRE impacts on human microglia within their physiological context - the brain environment. I will use an innovative xenotransplantation model, where microglia derived from patient-stem cells are injected into the brain of mice, combined with single-cell high throughput multi-omics technologies (i.e., transcriptome, proteome, and lipidomics). These approaches have never been applied before in the context of C9-associated diseases. I will profile the injected microglia by transcriptome and surface proteome analysis and evaluate the functional effect of the C9 HRE by analyzing microglial lysosomal fitness in vivo and in vitro. I predict that I will identify new pathological mechanisms relevant to understanding why the C9 mutation leads to FTD and ALS in patients. This could yield novel drug targets and biomarkers for clinical practice.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project