Do T cells link loss and gain-of-function mechanism in C9orf72 ALS/FTD?

This project investigates the role of T cells in the pathogenesis of ALS and FTD due to C9orf72 mutations, aiming to uncover mechanisms for new biomarkers and therapeutic targets.

Subsidie
€ 1.498.610
2024

Projectdetails

Introduction

Neurodegenerative diseases are the top 3 leading causes of death and are viewed now as systemic diseases. Adaptive immunity, including a T-cell response in the central nervous system (CNS), likely contributes to disease pathogenesis. How T cells are primed and recruited to the CNS is largely unexplored, due to the complexity of the process and lack of tools and animal models.

Research Focus

I will study these questions on the most common genetic form of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, a GGGGCC repeat expansion in the C9orf72 gene causes haploinsufficiency through reduced C9orf72 protein expression, and gain-of-function toxicities through repeat RNA and its translation to aggregating dipeptide repeats (DPRs). A synergistic role of these pathomechanisms is suspected but not clearly identified.

Hypothesis

I propose that T cells are the missing piece of the puzzle for the synergistic effects of C9orf72 haploinsufficiency and DPR toxicity. I will explore the following questions:

  1. Whether peripheral antigen-presenting cells (APCs) and CNS microglia present DPRs to prime antigen-specific T-cell response.
  2. Whether C9orf72 haploinsufficiency alters antigen presentation of microglia and APCs.
  3. Whether T cells mediate synergistic effects of C9orf72 haploinsufficiency and DPR toxicity.

Novel Contributions

This novel project for the first time addresses peripheral and CNS activation of T cells against DPRs in C9orf72 ALS/FTD and reveals a novel mechanism on the synergistic effect of C9orf72 haploinsufficiency and DPR toxicity.

Methodology

It offers a unique integration of neurobiological tools, immunological methods, and single-cell-level approaches. It brings solid evidence on the antigen presentation of endogenous aggregating protein to drive antigen-specific T-cell response, which will broaden the understanding of ALS/FTD and other neurodegenerative diseases.

Future Implications

This research presents a promising trajectory for the identification of new biomarkers, breakthrough therapeutic targets, and the development of novel interventions.

Financiële details & Tijdlijn

Financiële details

Subsidiebedrag€ 1.498.610
Totale projectbegroting€ 1.498.610

Tijdlijn

Startdatum1-4-2024
Einddatum31-3-2029
Subsidiejaar2024

Partners & Locaties

Projectpartners

  • DEUTSCHES ZENTRUM FUR NEURODEGENERATIVE ERKRANKUNGEN EVpenvoerder

Land(en)

Germany

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