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

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:

1. Haploinsufficiency through reduced C9orf72 protein expression.
2. 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:

a) Whether peripheral antigen-presenting cells (APCs) and CNS microglia present DPRs to prime antigen-specific T-cell response.
b) Whether C9orf72 haploinsufficiency alters antigen presentation of microglia and APCs.
c) 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.

Implications

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 Directions

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