Truncating mutations of SPAST associated with hereditary spastic paraplegia indicate greater accumulation and toxicity of the M1 isoform of spastin.
Truncating mutations of SPAST associated with hereditary spastic paraplegia indicate greater accumulation and toxicity of the M1 isoform of spastin.
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DOI：
10.1091/mbc.e17-01-0047
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发表时间：
2017-07-01
影响因子：
3.3
通讯作者：
Baas PW
中科院分区：
文献类型：
--
作者：
Solowska JM;Rao AN;Baas PW
SPAST基因是遗传性痉挛性截瘫的主要突变基因，它产生两种微管切断蛋白spastin亚型。截断的M1 spastin蛋白是有毒的，并且有可能在这些患者中积累。SPAST基因产生微管切断蛋白spastin的两个亚型（M1和M87），是遗传性痉挛性截瘫的主要突变基因。单倍不全是对这种疾病的一种普遍解释，部分原因是该基因的大部分致病突变都是截断的，预计只会产生极少量的缩短蛋白质。在这里，我们研究了两个这样的突变，N184X和S245X，我们的结果表明了另一种可能性。我们发现截断的M1蛋白可以积累到明显高于其截断的M87或野生型对应物的水平。让人想起我们早期对产生全长M1和M87蛋白的致病突变的研究，截断的M1对神经突生长的危害明显大于截断的M87，这对N184X和S245X都是如此。更大的毒性和累积倾向表明，随着时间的推移，截断的M1可能损害人类患者的皮质脊髓束。奇怪的是，N184X突变触发SPAST中第三个起始密码子的翻译重新启动，导致能够切断微管的新型M187 SPAST异构体的合成。因此，在这种突变的情况下，微管切断可能不会像以前假设的那样减少。
The SPAST gene, which produces two isoforms of the microtubule-severing protein spastin, is the chief gene mutated in hereditary spastic paraplegia. Truncated M1 spastin proteins are toxic and have the potential to accumulate in these patients. 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.