Rescue of lysosomal function as therapeutic strategy for SPG15 hereditary spastic paraplegia.

SPG15 is a hereditary spastic paraplegia (HSP) subtype caused by mutations in Spastizin, a protein encoded by the ZFYVE26 gene. Spastizin is involved in autophagosome maturation and autophagic lysosome reformation (ALR) and SPG15-related mutations lead to ALR defects with lysosome enlargement, free lysosomes depletion and autophagosome accumulation. Symptomatic and rehabilitative treatments are the only therapy currently available for patients. Here, we targeted autophagy and lysosomes in SPG15 patient-derived cells by using a library of autophagy-modulating compounds. We identified a rose of compounds, affecting intracellular calcium levels, the calcium-calpain pathway, or lysosomal functions, that reduced autophagosome accumulation. The six most effective compounds were tested in vivo in a new SPG15 loss of function Drosophila model that mimicked the reported SPG15 phenotype, with autophagosome accumulation, enlarged lysosomes, reduced free lysosomes, ALR defects and locomotor deficit. These compounds, namely verapamil, Bay K8644, 2',5'-dideoxyadenosine, trehalose, Small Molecule Enhancer of Rapamycin 28 (SMER28) and trifluoperazine, improved lysosome biogenesis and function in vivo, demonstrating that lysosomes are a key pharmacological target to rescue SPG15 phenotype. Among the others, the small molecule enhancer of autophagy SMER28 was the most effective, rescuing both ALR defects and locomotor deficit, and could be considered as a potential therapeutic compound for this HSP subtype.