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

Author:

Vantaggiato Chiara1ORCID,Orso Genny2,Guarato Giulia2,Brivio Francesca1,Napoli Barbara2,Panzeri Elena1,Masotti Simona1,Santorelli Filippo Maria3ORCID,Lamprou Maria4,Gumeni Sentiljana4,Clementi Emilio5,Bassi Maria Teresa1

Affiliation:

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. Department of Molecular Medicine, IRCCS Stella Maris Foundation, Calambrone , 56128 Pisa , Italy

4. Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens , Athens 15784 , Greece

5. Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco , ‘Luigi Sacco’ University Hospital, Università di Milano, Milan , Italy

Abstract

Abstract SPG15 is a hereditary spastic paraplegia subtype caused by mutations in Spastizin, a protein encoded by the ZFYVE26 gene. Spastizin is involved in autophagosome maturation and autophagic lysosome reformation and SPG15-related mutations lead to autophagic lysosome reformation defects with lysosome enlargement, free lysosome 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, which 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, autophagic lysosome reformation defects and locomotor deficit. These compounds, namely verapamil, Bay K8644, 2′,5′-dideoxyadenosine, trehalose, Small-Molecule Enhancer of Rapamycin 28 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 Rapamycin 28 was the most effective, rescuing both autophagic lysosome reformation defects and locomotor deficit, and could be considered as a potential therapeutic compound for this hereditary spastic paraplegia subtype.

Funder

Italian Ministry of Health

Fondazione Regionale Lombarda per la ricerca biomedica

FRRB

University of Padova

Fondazione Cariparo

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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