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Hum Mol Genet. 2016 Mar 15;25(6):1088-99. doi: 10.1093/hmg/ddv632. Epub 2016 Jan 6.

Conserved pharmacological rescue of hereditary spastic paraplegia-related phenotypes across model organisms.

Author information

1
CRCHUM and Department of Neuroscience and.
2
Institute for Neuroscience and Mental Health and Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada and.
3
CRCHUM and Department of Biochemistry, Université de Montréal, Montréal, Québec, Canada.
4
Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada and.
5
Montreal Neurological Institute and Hospital, McGill University, Montréal, Québec, Canada.
6
Institute for Neuroscience and Mental Health and Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada and fbolduc@ualberta.ca.

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.

PMID:
26744324
PMCID:
PMC4764191
DOI:
10.1093/hmg/ddv632
[Indexed for MEDLINE]
Free PMC Article

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