Age dependent dynamics of neuronal VAP ALS inclusions in the adult brain

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a progressive motor neuron disease that leads to motor control loss due to neuronal death. Of the ~30 genetic loci linked to familial ALS, VAPB (ALS8) was the 8th discovered. It encodes an ER membrane protein involved in maintaining membrane contact sites and protein trafficking. A proline-to-serine mutation at position 56 causes ALS in humans, while a similar mutation at position 58 (VAPP58S) is used to model ALS in flies. Mutant flies exhibit reduced lifespan, motor defects, and brain aggregates, whose density depends on mutant protein dose. Introducing a wild-type copy clears aggregates. Prior studies suggest autophagy and proteasomal system contribute to aggregate clearance, but how these pathways affect aggregate density over time remains unclear. We investigated the role of Atg1 and Ter94 (homologue of VCP in flies) in aggregate dynamics in the adult fly brain at different time points. Atg1 and Ter94 knockdown led to increased and decreased aggregate density, respectively, aligning with previous findings. Additionally, reduced motor ability correlated with increased aggregate density in autophagy-modulated flies. However, Ter94 modulation had minimal impact on aggregate density. This study provides a more detailed understanding of aggregate dynamics in the adult fly brain. Further exploration of interactions between Atg1, VAP, and Ter94 could help uncover the molecular mechanisms underlying aggregate formation and clearance, offering potential insights into ALS pathology