{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T14:14:02Z","timestamp":1787840042788,"version":"build-2784847793"},"reference-count":46,"publisher":"American Society for Cell Biology (ASCB)","issue":"13","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["MBoC"],"published-print":{"date-parts":[[2017,7]]},"abstract":"<jats:p>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 &gt;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.<\/jats:p>","DOI":"10.1091\/mbc.e17-01-0047","type":"journal-article","created":{"date-parts":[[2017,5,11]],"date-time":"2017-05-11T20:40:19Z","timestamp":1494535219000},"page":"1728-1737","source":"Crossref","is-referenced-by-count":40,"title":["Truncating mutations of\n                    <i>SPAST<\/i>\n                    associated with hereditary spastic paraplegia indicate greater accumulation and toxicity of the M1 isoform of spastin"],"prefix":"10.1091","volume":"28","author":[{"given":"Joanna M.","family":"Solowska","sequence":"first","affiliation":[{"name":"Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anand N.","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Anatomy, Drexel University College of Medicine, 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