Current theories fall short
The prevailing explanation for how HSP is caused cannot readily explain why most HSP is adult-onset, or why nerve degeneration localises to the corticospinal tracts when every cell in the body contains the genetic mutation.
This research challenges current theories: it establishes that different forms of mutated Spastin vary significantly in their toxicity and have opposite effects on microtubule dynamics. It provides details on the mechanism of the toxicity and may point the way for where to look for a cure.
Mutations to the SPG4 gene encoding the microtubule-severing protein spastin are the most common cause of hereditary spastic paraplegia. Haploinsufficiency, the prevalent model for the disease, cannot readily explain many of its key aspects, such as its adult onset or its specificity for the corticospinal tracts. Treatment strategies based solely on haploinsufficiency are therefore likely to fail. Toward developing effective therapies, here we investigated potential gain-of-function effects of mutant spastins.
The full-length human spastin isoform called M1 or a slightly shorter isoform called M87, both carrying the same pathogenic mutation C448Y, were expressed in three model systems: primary rat cortical neurons, fibroblasts, and transgenic Drosophila. Although both isoforms had ill effects on motor function in transgenic flies and decreased neurite outgrowth from primary cortical neurons, mutant M1 was notably more toxic than mutant M87.
The observed phenotypes did not result from dominant-negative effects of mutated spastins.
Studies in cultured cells revealed that microtubules can be heavily decorated by mutant M1 but not mutant M87. Microtubule-bound mutant M1 decreased microtubule dynamics, whereas unbound M1 or M87 mutant spastins increased microtubule dynamics. The alterations in microtubule dynamics observed in the presence of mutated spastins are not consistent with haploinsufficiency and are better explained by a gain-of-function mechanism. Our results fortify a model wherein toxicity of mutant spastin proteins, especially mutant M1, contributes to axonal degeneration in the corticospinal tracts. Furthermore, our results provide details on the mechanism of the toxicity that may chart a course toward more effective treatment regimens.
SOURCE: J Neurosci. 2014 Jan 29;34(5):1856-67. doi: 10.1523/JNEUROSCI.3309-13.2014. PMID: 24478365 [PubMed – in process] PMCID: PMC3905148 [Available on 2014/7/29]
Pathogenic Mutation of Spastin Has Gain-of-Function Effects on Microtubule Dynamics.
Solowska JM1, D’Rozario M, Jean DC, Davidson MW, Marenda DR, Baas PW.
1Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129, Department of Biology, Drexel University, Philadelphia, Pennsylvania 19104, and National High Magnetic Field Laboratory, Florida State University, Tallahassee, Florida 32310.