Abstract

Cell-to-Cell Propagation of Pathogenic Aberrant Dipeptide Repeat Proteins in C9orf72-Linked Amyotrophic Lateral Sclerosis

Davide Trotti, Professor, Scientific Director, Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson University

Nucleotide repeat expansions (NREs) are prevalent mutations in a multitude of neurodegenerative diseases. Abnormal translation of these repeat regions produces proteins that contribute to the pathogenesis of these diseases. However, the mechanisms and drivers of the aberrant translation are not well understood. Here we analyzed whether different cellular stressors promote these aberrant translations of peptides associated with the G4C2 hexanucleotide expansions in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that activating glutamate receptors or increasing neuronal activity trigger these aberrant translation of  neurotoxic peptides. In addition, we postulate that cell-to-cell transmission of these disease-linked aberrant peptides could be a modality by which toxic insults spread in disease-afflicted CNS areas in ALS and FTD. We are presenting evidence here using in vitro and in vivo approaches that indeed transmission of these aberrantly translated peptides occurs via exosomes and that transfer of injury could happen from the neuron of peptide formation to neighboring neurons but also to neurons connected in neuronal networks.