Conventional view of SPG4 cause challenged

Additional mechanism suggested


Peter Baas

Using a new HSP mouse that they bred, the HSP research team at Drexel University in the USA led by Peter Baas finds evidence for a toxic gain-of-function mechanism that affects microtubule stability in an opposite  way to the conventionally held view, namely a loss-of-function mechanism. They maintain that the loss-of-function makes the toxicity from the gain-of-function worse and indicates the need for a different approach to finding effective treatments.



Mutations of the SPAST gene, which encodes the microtubule-severing protein spastin, are the most common cause of Hereditary Spastic Paraplegia. Haploinsufficiency is the prevalent opinion as to the mechanism of the disease, but gain-of-function toxicity of the mutant proteins is another possibility.


Here, we report a new transgenic mouse (termed SPASTC448Y mouse) that is not haploinsufficient but expresses human spastin bearing the HSP pathogenic C448Y mutation. Expression of the mutant spastin was documented from fetus to adult, but gait defects reminiscent of Hereditary Spastic Paraplegia (not observed in spastin knockout mice) were adult-onset, as is typical of human patients.


Results of histological and tracer studies on the mouse are consistent with progressive dying-back of corticospinal axons, which is characteristic of the disease. The C448Y-mutated spastin alters microtubule stability in a manner that is opposite to the expectations of haploinsufficiency. Neurons cultured from the mouse display deficits in organelle transport typical of axonal degenerative diseases, and these deficits were worsened by depletion of endogenous mouse spastin.


These results on the SPASTC448Y mouse are consistent with a gain-of-function mechanism underlying Hereditary Spastic Paraplegia, with spastin haploinsufficiency exacerbating the toxicity of the mutant spastin proteins. These findings reveal the need for a different therapeutic approach than indicated by haploinsufficiency alone.


SOURCE: Hum Mol Genet. 2018 Dec 6. doi: 10.1093/hmg/ddy419. [Epub ahead of print] PMID: 30520996


Hereditary Spastic Paraplegia: gain-of-function mechanisms revealed by new transgenic mouse.


Qiang L1,2, Piermarini E1,2, Muralidharan H1, Yu W1, Leo L1, Hennessy LE3, Fernandes S1, Connors T1, Yates PL1, Swift M1, Zholudeva LV1, Lane MA1, Morfini G4, Alexander GM3, Heiman-Patterson TD3, Baas PW1.


1 Department of Neurobiology and Anatomy.

2 Co-first authors (equal contributions).

3 Department of Neurology Drexel University, College of Medicine 2900 Queen Lane, Philadelphia, PA.

4 Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL.

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