New crossbred SPG4 mouse holds great promise

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.

Asst Prof Liang Qiang (Oscar)

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.

Dr Emanuela Piermarini PhD

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

Emanuela Piermarini  1 Seyma Akarsu  1   2 Theresa Connors  1 Matthias Kneussel  3 Michael A Lane  1 Gerardo Morfini  4 Arzu Karabay  2 Peter W Baas  1 Liang Qiang  1

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.


    1. Editor’s Note: We have no information on that for the SPG4 mouse program at Drexel University. You could communicate your question directly to them.

        1. Editor’s Note: No, there has been no progress over the past three months. With the surge in COVID-19 across Australia that began in December due to the new Omicron strain, access to research laboratories was not possible for much of the time, given that these facilities are on a hospital campus with restrictions on personnel and movements, redirection of resources to cope with the pandemic and people taking their summer holidays. It is always a slow quarter with summer holidays, but this quarter research came to a full stop.

      1. Editor’s Note: UPDATE – One of the research team members responded to your question, “this compound has been shown to be neuroprotective. It increases acetylated alpha-tubulin, tyrosinated alpha-tubulin and phosphorylated alpha-tubulin, which are all aspects of microtubule stability. Dose level is an issue because, like noscapine and other tubulin drugs that can rectify imbalance and restore stability, high doses can overcorrect for imbalance, with potentially serious health implications.”

  1. Thank this team for working so hard on this! So many of us have suffered with HSP for way too long and need some hope for our future. Neurodegenerative diseases have been ignored for so long. I would love to hear that there is something for us. Dreaming that I will get a phone call soon saying that I am cured!

  2. Dear editor
    Can udca ursodeoxycholic acid work for hsp? I think yes. I have been reading daily publications of this drug for neurodegenerative disease, it can improve health of motor neurons.

  3. I have read that it can improve mitochondrial function and is an antiapoptopic agent which can reduce cell death and also inhibit ER stress
    Which can improve motor neurons.
    What’s your opinion?

  4. There are random studies I have read on the internet for MND, ALS and other types of neurodegenerative disease.

    1. Editor’s Note: UDCA has been studied as a treatment for some forms of impaired liver function historically, and more recently for neurodegenerative disease as you mention, with the major focus being on Parkinson’s Disease (PD) where it appears a small clinical trial is currently underway The main mode of action appears to be reducing impairment in mitochondrial function, reducing autophagy (waste processing in cells) and reducing apoptosis (cell death). Even with these studies, the researchers state that the pathways of treatment effect in PD are unclear. There appears to be no data or information on the potential for UDCA to treat the HSPs, however it may be most relevant to those forms of HSP where mitochondrial impairment is the main disease-causing mechanism such as in SPG7 and 31.

    1. Editor’s Note: Yes, there is evidence that UDCA can relieve ER stress, however the place and significance of ER stress in the disease mechanism of SPG6 is unclear. Any drug candidate for any form of HSP would need to target the primary impairment for the particular type, rather than a downstream or parallel impairment. The bottom line is that these questions do not have answers at this point for this drug regarding SPG6. To get these answers requires a focused research program with a very significant commitment of people and money.

  5. Thanks Yes i have read that it can also reduce upr and er
    Can we try the drug udca as its safe drug with stomach related side effects.
    Even trials are going with tudca its taurine congugated udca for parkinsons and als

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