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Truncating mutations of SPAST associated with hereditary spastic paraplegia indicate greater accumulation and toxicity of the M1 isoform of spastin
Journal article   Open access   Peer reviewed

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

Joanna M Solowska, Anand N Rao and Peter W Baas
Molecular biology of the cell, v 28(13), pp 1728-1737
01 Jul 2017
DOI: https://doi.org/10.1091/mbc.E17-01-0047
PMID: 28495799
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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https://doi.org/10.1091/mbc.e17-01-0047View
Published, Version of Record (VoR)CC BY-NC-SA V4.0,  Open

Abstract

Animals Cells, Cultured Codon, Nonsense Haploinsufficiency Humans Microtubules - metabolism Mutagenesis, Site-Directed Neurites - metabolism Neurons - metabolism Protein Isoforms Rats Spastic Paraplegia, Hereditary - genetics Spastic Paraplegia, Hereditary - metabolism Spastin - genetics Spastin - metabolism
The 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 , 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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