Aim to use for testing SPG4 therapies
Researchers have developed a crossbred mouse that is the best prospect yet for the testing of potential therapies for SPG4 HSP in animals.
The crossbred mouse exhibits both the cellular and mobility features of SPG4 HSP in humans. The crossbred mouse was the result of breeding a mouse that produced no spastin protein with a mouse that has human mutant spastin. Each mouse separately had something in common with SPG4 in humans, but the crossbred mouse exhibited all the features combined.
The team at Drexel University in Pennsylvania, USA, have established a highly regarded centre of excellence in SPG4 research over several years. Assured funding in the near to midterm will hopefully see the development and testing of SPG4 therapies on these animal models in the not-too-distant future.
Hereditary Spastic Paraplegia (HSP) is a disease in which dieback degeneration of corticospinal tracts, accompanied by axonal swellings, leads to gait deficiencies. SPG4-HSP, the most common form of the disease, results from mutations of SPAST, which is the gene that encodes spastin, a microtubule-severing protein.
The lack of a vertebrate model that recapitulates both the etiology and symptoms of SPG4-HSP has stymied the development of effective therapies for the disease. hSPAST-C448Y mice, which express human mutant spastin at the ROSA26 locus, display corticospinal dieback and gait deficiencies, but not axonal swellings. On the other hand, Spast-knockout mice display axonal swellings but not corticospinal dieback or gait deficiencies. One possibility is that reduced spastin function, resulting in axonal swellings, is not the cause of the disease, but exacerbates the toxic effects of the mutant protein.
To explore this idea, Spast-knockout and hSPAST-C448Y mice were crossbred, and the offspring were compared to the parental lines via histological and behavioral analyses. The crossbred animals displayed axonal swellings, as well as earlier onset, worsened gait deficiencies and corticospinal dieback compared to the hSPAST-C448Y mouse. These results, together with observations on changes in HDAC6 and tubulin modifications in the axon, indicate that each of these three transgenic mouse lines is valuable for investigating a different component of the disease pathology. Moreover, the crossbred mice are the best vertebrate model to date for testing potential therapies for SPG4-HSP.
SOURCE: Hum Mol Genet. 2021 Dec 22;ddab367. doi: 10.1093/hmg/ddab367. Online ahead of print. PMID: 34935948 © The Author(s) 2021. Published by Oxford University Press. All rights reserved.
Modeling gain-of-function and loss-of-function components of SPAST-based hereditary spastic paraplegia using transgenic mice
1. Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
2. Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul, Turkey.
3. Department of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany.
4. Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA.