SPG3A human stem cell neuron fixed

Microtubule-binding agent works on axon growth defects


Craig Blackstone
Craig Blackstone

A US research team led by global HSP authority Craig Blackstone has corrected axon growth defects in human stem cell neurons with SPG3A HSP. This was achieved using vinblastine, which is not a candidate drug for treatment as it does not cross the blood-brain barrier.


Hereditary spastic paraplegias are a large, diverse group of neurological disorders (SPG1-71) with the unifying feature of prominent lower extremity spasticity, owing to a length-dependent axonopathy of corticospinal motor neurons.

The most common early-onset form of pure, autosomal dominant hereditary spastic paraplegia is caused by mutation in the ATL1 gene encoding the atlastin-1 GTPase, which mediates homotypic fusion of ER tubules to form the polygonal ER network. We have identified a p.Pro342Ser mutation in a young girl with pure SPG3A. This residue is in a critical hinge region of atlastin-1 between its GTPase and assembly domains, and it is conserved in all known eukaryotic atlastin orthologs.

We produced induced pluripotent stem cells from skin fibroblasts and differentiated these into forebrain neurons to generate a human neuronal model for SPG3A. Axons of these SPG3A neurons showed impaired growth, recapitulating axonal defects in atlastin-1-depleted rat cortical neurons and impaired root hair growth in loss-of-function mutants of the ATL1 ortholog rhd3 in the plant Arabidopsis. Both the microtubule cytoskeleton and tubular ER are important for mitochondrial distribution and function within cells, and SPG3A neurons showed alterations in mitochondrial motility. Even so, it is not clear whether this change is involved in disease pathogenesis.

The SPG3A axon growth defects could be rescued with microtubule-binding agents, emphasizing the importance of tubular ER interactions with the microtubule cytoskeleton in hereditary spastic paraplegia pathogenesis. The prominent alterations in axon growth in SPG3A neurons may represent a particularly attractive target for suppression in screens for novel pharmacologic agents.

SOURCE: Hum Mol Genet 2014 Jun 6. pii: ddu280. [Epub ahead of print] Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

PMID: 24908668 [PubMed – as supplied by publisher]

Pharmacologic rescue of axon growth defects in a human iPSC model of hereditary spastic paraplegia SPG3A.

Zhu PP1, Denton KR2, Pierson TM3, Li XJ4, Blackstone C1.

1Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.

  • 2Department of Neuroscience and.

  • 3Departments of Pediatrics and Neurology and the Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

  • 4Department of Neuroscience and The Stem Cell Institute, University of Connecticut Health Center, Farmington, CT 06030, USA and [email protected].


  1. Hi I have HSP SPG3A and my two boys aged 16 and 14. Does this mean that there is a treatment to help? Is there an age cutoff for the treatment? We are in Australia Sydney

    1. Editor’s Note: No, it is not a treatment. Certain compounds are well known to impact microtubules in cells and one of these, vinblastine, was used to restore the impairments found in the SPG3A neurons in this study. A similar result was found in the HSP research done at Griffith University in Brisbane using SPG4 stem cells. Vinblastine is not a candidate for treatment as it cannot cross the blood-brain barrier and get into the location in the brain stem where any potential treatment needs to be to do its work. Trying to find suitable drugs is what the Griffith University HSP research is now all about. This SPG3A research may indicate that it would be possible for a drug that is effective with SPG4 to also be effective with SPG3A… but I emphasise the word “may”.

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