Mechanism unrelated to microtubule-severing ability
A certain group of missense mutations in spastin have been identified in this study to be a likely cause of HSP as they are associated with abnormalities in structure, function and movement of lysosomes, an important organelle in neurons. Notably, these mutations do not directly affect spastin’s microtubule-severing activity, which is the normal disease-causing mechanism of spastin mutations, and so represent a new molecular mechanism for causing this type of HSP.
The hereditary spastic paraplegias (HSPs) are genetic motor neuron diseases characterized by progressive degeneration of corticospinal tract axons. Mutations in SPAST, encoding the microtubule-severing ATPase spastin, are the most common causes of HSP. The broad SPAST mutational spectrum indicates a haploinsufficiency pathogenic mechanism in most cases. Most missense mutations cluster in the ATPase domain, where they disrupt the protein’s ability to sever microtubules. However, several putative missense mutations in the protein’s microtubule interacting and trafficking (MIT) domain have also been described, but the pathogenicity of these mutations has not been verified with functional studies. Spastin promotes endosomal tubule fission, and defects in this lead to lysosomal enzyme mistrafficking and downstream lysosomal abnormalities.
We investigated the function of three disease-associated spastin MIT mutants and found that none was able to promote normal endosomal tubule fission, lysosomal enzyme receptor trafficking, or lysosomal morphology. One of the mutations affected recruitment of spastin to endosomes, a property that requires the canonical function of the MIT domain in binding endosomal sorting complex required for transport (ESCRT)-III proteins. However, the other mutants did not affect spastin’s endosomal recruitment, raising the possibility of pathologically important non-canonical roles for the MIT domain.
In conclusion, we demonstrate that spastin MIT mutants cause functional abnormalities related to the pathogenesis of HSP. These mutations do not directly affect spastin’s microtubule-severing capacity, and so we identify a new molecular pathological mechanism by which spastin mutations may cause disease.
SOURCE: Front Neurosci. 2019 Nov 8;13:1179. doi: 10.3389/fnins.2019.01179. eCollection 2019. PMID: 31787869 Copyright © 2019 Allison, Edgar and Reid.
Spastin MIT Domain Disease-Associated Mutations Disrupt Lysosomal Function.
1 Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
2 Department of Pathology, University of Cambridge, Cambridge, United Kingdom.