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

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 CNS is largely unexplored, due to the complexity of the process and lack of tools and animal models.

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.

I propose that T cells are the missing piece of the puzzle for the synergistic effects of C9orf72 haploinsufficiency and DRP toxicity and 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 synergic effects of C9orf72 haploinsufficiency and DRP toxicity.

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

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