Biomarkers investigated in animal models
This Canadian study demonstrates that various chemical compounds known to alleviate stress on cellular structures partially reverse impaired HSP-like motor function in laboratory worms, flies and fish.
The study also provides clues to potential biomarkers, which are vital to establish as measures of HSP status and to gauge changes due to treatment if and when human HSP clinical trials are undertaken.
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.
SOURCE: Hum Mol Genet. 2016 Jan 6. pii: ddv632. [Epub ahead of print] © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]. PMID: 26744324 [PubMed – as supplied by publisher]
Conserved pharmacological rescue of hereditary spastic paraplegia-related phenotypes across model organisms.
Julien C1, Lissouba A1, Madabattula S2, Fardghassemi Y3, Rosenfelt C4, Androschuk A4, Strautman J2, Wong C4, Bysice A4, O’Sullivan J4, Rouleau GA5, Drapeau P1, Parker JA1, Bolduc FV6.
1CRCHUM and Department of Neuroscience, Université de Montréal, Montréal, Québec, Canada.
2Institute for Neuroscience and Mental Health, University of Alberta, Canada Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
3CRCHUM and Department of Biochemistry, Université de Montréal, Montréal, Québec, Canada.
4Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
5Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
6Institute for Neuroscience and Mental Health, University of Alberta, Canada Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada [email protected].