Defective axonal transport of endo-lysosomes and dense core vesicles in a Drosophila model of C9-ALS/FTD

A GGGGCC (G₄C₂) repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although disruptions in axonal transport are implicated in the pathogenesis of multiple neurodegenerative diseases, the underlying mechanisms causing these defects remain unclear. Here, we performed live imaging of Drosophila motor neurons expressing expanded G₄C₂ repeats in third-instar larvae and investigated the axonal transport of multiple organelles in vivo. Expression of expanded G₄C₂ repeats causes an increase in static axonal lysosomes, while it impairs trafficking of late endosomes (LEs) and dense core vesicles (DCVs). Surprisingly, however, axonal transport of mitochondria is unaffected in motor axons expressing expanded G₄C₂ repeats. Thus, our data indicate that expanded G₄C₂ repeat expression differentially impacts axonal transport of vesicular organelles and mitochondria in Drosophila models of C9orf72-associated ALS/FTD.