Conserved pharmacological rescue of hereditary spastic paraplegia-related phenotypes across model organisms
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 SP...
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Published in | Human molecular genetics Vol. 25; no. 6; pp. 1088 - 1099 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Oxford University Press
15.03.2016
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The first three authors are co-first authors. |
ISSN: | 0964-6906 1460-2083 1460-2083 |
DOI: | 10.1093/hmg/ddv632 |