Atlastin-1 regulates endosomal tubulation and lysosomal proteolysis in human cortical neurons

• DOI: 10.1101/2024.02.29.582512
• Publication Date: 2024-03-01T08:05:12Z
• Authors: Eliska Zlamalova; Catherine Rodger; Francesca Greco; Julia Kleniuk; Aishwarya G. Nada...; Zuzana Kadlecova; Evan Reid
• Keywords: Proteolysis

Abstract Mutation of the ATL1 gene is one most common causes hereditary spastic paraplegia (HSP), a group genetic neurodegenerative conditions characterised by distal axonal degeneration corticospinal tract axons. Atlastin-1, protein encoded , three mammalian atlastins, which are homologous dynamin-like GTPases that control endoplasmic reticulum (ER) morphology fusing tubules to form three-way junctions characterise ER networks. However, it not clear whether atlastin-1 required for correct in human neurons and if so what functional consequences lack are. Using CRISPR-inhibition we generated cortical lacking atlastin-1. We demonstrate was altered these neurons, with reduced number junctions. Neurons had longer endosomal tubules, suggestive defective tubule fission. This accompanied lysosomal proteolytic capacity. As well as demonstrating our results indicate classical ER-shaping such may cause tubulation dysfunction. Furthermore, they strengthen idea lysosome function contributes pathogenesis broad HSPs, including those where primary localisation involved at endolysosomal system.