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Truncating mutations of SPAST associated with hereditary spastic paraplegia indicate greater accumulation and toxicity of the M1 isoform of spastin

The SPAST gene, which produces two isoforms (M1 and M87) of the microtubule-severing protein spastin, is the chief gene mutated in hereditary spastic paraplegia. Haploinsufficiency is a popular explanation for the disease, in part because most of the >200 pathogenic mutations of the gene are trun...

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Autores principales: Solowska, Joanna M., Rao, Anand N., Baas, Peter W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491181/
https://www.ncbi.nlm.nih.gov/pubmed/28495799
http://dx.doi.org/10.1091/mbc.E17-01-0047
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author Solowska, Joanna M.
Rao, Anand N.
Baas, Peter W.
author_facet Solowska, Joanna M.
Rao, Anand N.
Baas, Peter W.
author_sort Solowska, Joanna M.
collection PubMed
description The SPAST gene, which produces two isoforms (M1 and M87) of the microtubule-severing protein spastin, is the chief gene mutated in hereditary spastic paraplegia. Haploinsufficiency is a popular explanation for the disease, in part because most of the >200 pathogenic mutations of the gene are truncating and expected to produce only vanishingly small amounts of shortened proteins. Here we studied two such mutations, N184X and S245X, and our results suggest another possibility. We found that the truncated M1 proteins can accumulate to notably higher levels than their truncated M87 or wild-type counterparts. Reminiscent of our earlier studies on a pathogenic mutation that generates full-length M1 and M87 proteins, truncated M1 was notably more detrimental to neurite outgrowth than truncated M87, and this was true for both N184X and S245X. The greater toxicity and tendency to accumulate suggest that, over time, truncated M1 could damage the corticospinal tracts of human patients. Curiously, the N184X mutation triggers the reinitiation of translation at a third start codon in SPAST, resulting in synthesis of a novel M187 spastin isoform that is able to sever microtubules. Thus microtubule severing may not be as reduced as previously assumed in the case of that mutation.
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spelling pubmed-54911812017-09-16 Truncating mutations of SPAST associated with hereditary spastic paraplegia indicate greater accumulation and toxicity of the M1 isoform of spastin Solowska, Joanna M. Rao, Anand N. Baas, Peter W. Mol Biol Cell Articles The SPAST gene, which produces two isoforms (M1 and M87) of the microtubule-severing protein spastin, is the chief gene mutated in hereditary spastic paraplegia. Haploinsufficiency is a popular explanation for the disease, in part because most of the >200 pathogenic mutations of the gene are truncating and expected to produce only vanishingly small amounts of shortened proteins. Here we studied two such mutations, N184X and S245X, and our results suggest another possibility. We found that the truncated M1 proteins can accumulate to notably higher levels than their truncated M87 or wild-type counterparts. Reminiscent of our earlier studies on a pathogenic mutation that generates full-length M1 and M87 proteins, truncated M1 was notably more detrimental to neurite outgrowth than truncated M87, and this was true for both N184X and S245X. The greater toxicity and tendency to accumulate suggest that, over time, truncated M1 could damage the corticospinal tracts of human patients. Curiously, the N184X mutation triggers the reinitiation of translation at a third start codon in SPAST, resulting in synthesis of a novel M187 spastin isoform that is able to sever microtubules. Thus microtubule severing may not be as reduced as previously assumed in the case of that mutation. The American Society for Cell Biology 2017-07-01 /pmc/articles/PMC5491181/ /pubmed/28495799 http://dx.doi.org/10.1091/mbc.E17-01-0047 Text en © 2017 Solowska et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Solowska, Joanna M.
Rao, Anand N.
Baas, Peter W.
Truncating mutations of SPAST associated with hereditary spastic paraplegia indicate greater accumulation and toxicity of the M1 isoform of spastin
title Truncating mutations of SPAST associated with hereditary spastic paraplegia indicate greater accumulation and toxicity of the M1 isoform of spastin
title_full Truncating mutations of SPAST associated with hereditary spastic paraplegia indicate greater accumulation and toxicity of the M1 isoform of spastin
title_fullStr Truncating mutations of SPAST associated with hereditary spastic paraplegia indicate greater accumulation and toxicity of the M1 isoform of spastin
title_full_unstemmed Truncating mutations of SPAST associated with hereditary spastic paraplegia indicate greater accumulation and toxicity of the M1 isoform of spastin
title_short Truncating mutations of SPAST associated with hereditary spastic paraplegia indicate greater accumulation and toxicity of the M1 isoform of spastin
title_sort truncating mutations of spast associated with hereditary spastic paraplegia indicate greater accumulation and toxicity of the m1 isoform of spastin
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491181/
https://www.ncbi.nlm.nih.gov/pubmed/28495799
http://dx.doi.org/10.1091/mbc.E17-01-0047
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