New explanation for SPG4 causal mechanism

Posted - September 2019 in Research Highlights

Both too little and too much might be to blame

 

Leading cell biologist and HSP researcher Peter Baas says that both sides are right in their seemingly opposing claims that too little Spastin causes HSP or too much of a toxic form of Spastin causes HSP. Dr Baas proposes that the lack of one type of the Spastin protein makes the neurons vulnerable and then either a second toxic type of Spastin protein or proteins generated by other genes affected by the Spastin mutation take effect, without being able to cause disease on their own.

 

Abstract

Mutations of the SPAST gene are the chief cause of hereditary spastic paraplegia. Controversy exists in the medical community as to whether the etiology of the disease is haploinsufficiency or toxic gain-of-function properties of the mutant spastin proteins.

In recognition of strong reasons that support each possible mechanism, here we present a novel perspective, based in part on new studies with mouse models and in part on the largest study to date on patients with the disease. We posit that haploinsufficiency does not cause the disease but makes the corticospinal tracts vulnerable to a second hit, which is usually the mutant spastin proteins but could also be proteins generated by mutations of other genes that may or may not cause the disease on their own.

SOURCE:   Cytoskeleton (Hoboken). 2019 Apr;76(4):289-297. doi: 10.1002/cm.21528. Epub 2019 Jul 3. © 2019 Wiley Periodicals, Inc. PMID: 31108029

New hypothesis for the etiology of SPAST-based hereditary spastic paraplegia.

Qiang L1, Piermarini E1, Baas PW1.

1 Department of Neurobiology and Anatomy, Drexel University, College of Medicine, Philadelphia, Pennsylvania.

 


 

… and another study on Spastin

Spastin role in brain development

 

Regulatory function at early developmental stages

 

Abstract

Spastin is generally known as a microtubule-severing enzyme and its association with axonal degeneration in corticospinal neurons leading to spasticity and spastic gait. In this study, its role in brain development, through regulation of neural stem cell functions in early developmental stages, is described.

Spastin is a microtubule-severing enzyme encoded by SPAST, which is broadly expressed in various cell types originated from multiple organs. Even though SPAST is well known as a regulator of the axon growth and arborization in neurons and a genetic factor of hereditary spastic paraplegia, it also takes part in a wide range of other cellular functions including the regulation of cell division and proliferation.

In this study, we investigated a novel biological role of spastin in developing brain using Spast deficient mouse embryonic neural stem cells (NSCs) and perinatal mouse brain. We found that the expression of spastin begins at early embryonic stages in mouse brain. Using Spast shRNA treated NSCs and mouse brain, we showed that Spast deficiency leads to decrease of NSC proliferation and neuronal lineage differentiation. Finally, we found that spastin controls NSC proliferation by regulating microtubule dynamics in primary cilia.

Collectively, these data demonstrate that spastin controls brain development by the regulation of NSC functions at early developmental stages.

SOURCE: Neuroscience. 2019 Jul 15;411:76-85. doi: 10.1016/j.neuroscience.2019.05.024. Epub 2019 May 29. Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved. PMID: 31150727

Spastin Contributes to Neural Development through the Regulation of Microtubule Dynamics in the Primary Cilia of Neural Stem Cells.

Jeong B1, Kim TH2, Kim DS3, Shin WH4, Lee JR5, Kim NS1, Lee DY6.

1 Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, South Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, South Korea.

2 Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, South Korea.

3 Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, South Korea; Department of Bioinformatics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, South Korea.

4 Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon 34114, South Korea.

5 Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, South Korea; Department of Biomolecular Science, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, South Korea.

6 Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, South Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, South Korea. Electronic address: [email protected]

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