In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary Spastic Paraplegia Type SPG11

摘要: Hereditary spastic paraplegia (HSP) is characterized by a dying back degeneration of corticospinal axons which leads to progressive weakness and spasticity the legs. SPG11 most common autosomal-recessive form HSPs caused mutations in SPG11. A recent vitro study suggested that Spatacsin, respective gene product, needed for recycling lysosomes from autolysosomes, process known as autophagic lysosome reformation. The relevance this observation hereditary paraplegia, however, has remained unclear. Here, we report disruption Spatacsin mice indeed causes paraplegia-like phenotypes with loss cortical neurons Purkinje cells. Degenerating accumulate autofluorescent material, stains lysosomal protein Lamp1 p62, marker substrate destined be degraded autophagy, hence appears related autolysosomes. Supporting more generalized defect levels lipidated LC3 are increased knockout mouse embryonic fibrobasts (MEFs). Though distinct parameters function like processing cathepsin D pH preserved, numbers reduced MEFs recovery during sustained starvation impaired consistent Because cells vivo, propose decreased number available fusion autophagosomes impairs autolysosomal clearance, results accumulation undegraded material finally death particularly sensitive motoneurons mice.