Drug candidates for treatment identified
Lysosomes have been identified as a key pharmacological target in this study that sheds light on the disease-causing mechanism in SPG15.
Lysosome depletion and impairment together with other cellular impairments were identified in patient-derived cells and also in SPG15-bred fruit flies that also showed mobility impairment.
The six most effective compounds tested on the fruit flies improved lysosome numbers and function, whilst the seventh compound also improved impaired mobility in the flies.
These compounds could be considered as potential therapeutic drugs for SPG15 HSP.
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). 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.
SOURCE: Brain. 2022 Aug 27;awac308. doi: 10.1093/brain/awac308. Online ahead of print. PMID: 36029068 © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.
Rescue of lysosomal function as therapeutic strategy for SPG15 hereditary spastic paraplegia
Chiara Vantaggiato 1 , Genny Orso 2 , Giulia Guarato 2 , Francesca Brivio 1 , Barbara Napoli 2 , Elena Panzeri 1 , Simona Masotti 1 , Filippo Maria Santorelli 3 , Maria Lamprou 4 , Sentiljana Gumeni 4 , Emilio Clementi 5 , Maria Teresa Bassi 1
1. Scientific Institute IRCCS E. Medea, Laboratory of Molecular Biology, 23842 Bosisio Parini, Lecco, Italy.
2. Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo E. Meneghetti 2, Padova, Italy.
3. IRCCS Stella Maris Foundation, Calambrone, Pisa, 56128, Italy.
4. Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.
5. Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, “Luigi Sacco” University Hospital, Università di Milano, Milan, Italy.