Targeting C9ORF72 function in ALS/FTD

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases with comparably high lifetime risk and substantial phenotypic variability. Socioeconomic needs for advancing treatment of these diseases in aging societies are therefore more pressing than ever.

While the past decade has witnessed progress in defining molecular alterations associated with ALS/FTD, many uncertainties remain and limit the development of therapies.Our transnational team proposes a multidisciplinary approach to test the central hypothesis that C9ORF72 mutation causes ALS/FTD via combined loss of physiological and gain of toxic functions that converge on the endolysosome system and the generation of extracellular vesicles.

TAGCNINE comprises a multi-national group of experts in neuroscience, biochemistry, cell biology, neurology and epidemiology.

We will combine studies in human iPSC-derived neurons, neuron-glial networks, and brain organoids with microfluidics, to test this hypothesis.

By integrating molecular analyses in human models of increasing complexity with information derived from epidemiological and biochemical data from ALS/FTD patients, we aim to unravel the cascade of events by which loss of C9ORF72 and C9ORF72 hexanucleotide repeat expansion in motoneurons and in glia cause neurodegeneration.

The ultimate goal is to predict nodes and reveal novel targets in ALS/FTD and lay the foundations of a pre-clinical drug testing platform.