title: Conserved pharmacological rescue of hereditary spastic paraplegia-related phenotypes across model organisms.
abstract: Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases causing progressive gait dysfunction. Over 50 genes have now been associated with HSP. Despite the recent explosion in genetic knowledge, HSP remains without pharmacological treatment. Loss-of-function mutation of the SPAST gene, also known as SPG4, is the most common cause of HSP in patients. SPAST is conserved across animal species and regulates microtubule dynamics. Recent studies have shown that it also modulates endoplasmic reticulum (ER) stress. Here, utilizing null SPAST homologues in C. elegans, Drosophila and zebrafish, we tested FDA-approved compounds known to modulate ER stress in order to ameliorate locomotor phenotypes associated with HSP. We found that locomotor defects found in all of our spastin models could be partially rescued by phenazine, methylene blue, N-acetyl-cysteine, guanabenz and salubrinal. In addition, we show that established biomarkers of ER stress levels correlated with improved locomotor activity upon treatment across model organisms. Our results provide insights into biomarkers and novel therapeutic avenues for HSP.
authors.affiliation: CRCHUM and Department of Neuroscience and.
authors.forename: Carl
authors.initials: C
authors.lastname: Julien
authors.affiliation: CRCHUM and Department of Neuroscience and.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lissouba
authors.affiliation: Institute for Neuroscience and Mental Health and Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada and.
authors.forename: Surya
authors.initials: S
authors.lastname: Madabattula
authors.affiliation: CRCHUM and Department of Biochemistry, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Fardghassemi
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada and.
authors.forename: Cory
authors.initials: C
authors.lastname: Rosenfelt
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada and.
authors.forename: Alaura
authors.initials: A
authors.lastname: Androschuk
authors.affiliation: Institute for Neuroscience and Mental Health and Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada and.
authors.forename: Joel
authors.initials: J
authors.lastname: Strautman
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada and.
authors.forename: Clement
authors.initials: C
authors.lastname: Wong
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bysice
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada and.
authors.forename: Julia
authors.initials: J
authors.lastname: O'sullivan
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montréal, Québec, Canada.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.affiliation: CRCHUM and Department of Neuroscience and.
authors.forename: Pierre
authors.initials: P
authors.lastname: Drapeau
authors.affiliation: CRCHUM and Department of Neuroscience and.
authors.forename: J Alex
authors.initials: JA
authors.lastname: Parker
authors.affiliation: Institute for Neuroscience and Mental Health and Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada and fbolduc@ualberta.ca.
authors.forename: François V
authors.initials: FV
authors.lastname: Bolduc
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D000818:Animals; D017173:Caenorhabditis elegans; D004195:Disease Models, Animal; D004330:Drosophila; D004721:Endoplasmic Reticulum / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D005260:Female; D006801:Humans; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D010619:Phenazines / Q000494:pharmacology; D010641:Phenotype; D015419:Spastic Paraplegia, Hereditary / Q000188:drug therapy* / Q000235:genetics; D015027:Zebrafish
chemical_list: D010619:Phenazines; C000598831:phenazine; D000251:Adenosine Triphosphatases