Defective axonal transport of endo‐lysosomes and dense core vesicles in a Drosophila model of C9‐ALS/FTD. (17th August 2022)

• Record Type: Journal Article
• Authors: Sung, Hyun; Lloyd, Thomas E.
• Is Part Of: Traffic. Volume 23:Number 9(2022)
• Page Start: 430
• Page End: 441
• Publication Date: 2022-08-17
• Subjects: axonal transport -- C9‐ALS/FTD -- motor neuron -- drosophila -- endo‐lysosome -- mitochondria -- dense core vesicle; Biological transport -- Periodicals; 571.6
• DOI: 10.1111/tra.12861
• Languages: English
• ISSNs: 1398-9219

Abstract

Abstract: A GGGGCC (G4 C2 ) 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 G4 C2 repeats in third‐instar larvae and investigated the axonal transport of multiple organelles in vivo. Expression of expanded G4 C2 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 G4 C2 repeats. Thus, our data indicate that expanded G4 C2 repeat expression differentially impacts axonal transport of vesicular organelles and mitochondria in Drosophila models of C9orf72 ‐associated ALS/FTD. Synopsis: Axonal transport is an indispensable cellular process responsible for movement of cargos along the axon in order to maintain the long‐distance communication between soma and synapses. For decades, it has been reported that axonal transport defects are observed in motor neuron diseases, including ALS. In this study, we report that Drosophila motor neurons expressing expanded GGGGCC repeats to model C9orf72 ‐associated ALS show specific disruptions in organelle transport for endo‐lysosomes and dense core vesicles, but not for mitochondria. Abstract : The expansion of GGGGCC repeats in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and FTD. Here, we performed live imaging of Drosophila larval motor neurons expressing GGGGCC repeats, and investigated axonal transport of multiple organelles in vivo. We have identified that the affected motor neurons show specific disruptions in organelle trafficking for endo‐lysosomes and dense core vesicles, but not for mitochondria. Image was generated using bioRENDER