PUBLICATION
Conserved pharmacological rescue of hereditary spastic paraplegia-related phenotypes across model organisms
- Authors
- Julien, C., Lissouba, A., Madabattula, S., Fardghassemi, Y., Rosenfelt, C., Androschuk, A., Strautman, J., Wong, C., Bysice, A., O'Sullivan, J., Rouleau, G.A., Drapeau, P., Parker, J.A., Bolduc, F.V.
- ID
- ZDB-PUB-160109-6
- Date
- 2016
- Source
- Human molecular genetics 25(6): 1088-99 (Journal)
- Registered Authors
- Drapeau, Pierre
- Keywords
- none
- MeSH Terms
-
- Adenosine Triphosphatases/genetics
- Animals
- Caenorhabditis elegans
- Disease Models, Animal*
- Drosophila
- Endoplasmic Reticulum/drug effects
- Endoplasmic Reticulum Stress/drug effects
- Endoplasmic Reticulum Stress/genetics
- Female
- Humans
- Locomotion/drug effects
- Locomotion/genetics
- Microtubules/drug effects
- Microtubules/metabolism
- Mutation
- Phenazines/pharmacology
- Phenotype
- Spastic Paraplegia, Hereditary/drug therapy*
- Spastic Paraplegia, Hereditary/genetics
- Zebrafish
- PubMed
- 26744324 Full text @ Hum. Mol. Genet.
Citation
Julien, C., Lissouba, A., Madabattula, S., Fardghassemi, Y., Rosenfelt, C., Androschuk, A., Strautman, J., Wong, C., Bysice, A., O'Sullivan, J., Rouleau, G.A., Drapeau, P., Parker, J.A., Bolduc, F.V. (2016) Conserved pharmacological rescue of hereditary spastic paraplegia-related phenotypes across model organisms. Human molecular genetics. 25(6):1088-99.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping