Formation and persistence of polyglutamine aggregates in mistranslating cells.
Formation and persistence of polyglutamine aggregates in mistranslating cells.
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DOI：
10.1093/nar/gkab898
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发表时间：
2021-11-18
影响因子：
14.9
通讯作者：
O'Donoghue P
中科院分区：
文献类型：
--
作者：
Lant JT;Kiri R;Duennwald ML;O'Donoghue P
在神经退行性疾病中，包括具有已知致病等位基因的病理，改变其严重程度或发病年龄的遗传因素尚不完全清楚。我们最近记录了人类群体中转移RNA （tRNA）突变的意外流行，包括导致氨基酸错误结合的变异。我们假设误译tRNA会加剧毒性并改变亨廷顿氏病致病等位基因的分子病理学。我们鉴定了tRNAPro突变体与丙氨酸错误翻译脯氨酸密码子，以及tRNASer突变体，包括在约2%的人群中发现的tRNASerAGA G35A突变体与苯丙氨酸反密码子（tRNASerAAA）。tRNAPro突变体在神经元细胞中引起有害的亨廷顿多谷氨酰胺（polyQ）等位基因的合成毒性。tRNASerAAA变异具有蛋白酶体抑制的合成毒性，但没有增强亨廷顿蛋白等位基因的毒性。用丝氨酸错误翻译苯丙氨酸或脯氨酸密码子的细胞显著降低了蛋白质合成率。误译细胞在形成不溶性聚q聚集体方面缓慢但有效，在蛋白质和聚集体降解方面存在缺陷，并且对神经保护性综合应激反应抑制剂（ISRIB）具有抗性。我们的研究发现，在神经退行性疾病的细胞模型中，误译tRNA变异是减缓蛋白质聚集动力学、抑制聚集清除和增加耐药性的遗传因素。在1.8%的人群中发现的人类tRNASer变体指导丝氨酸错误结合并抑制蛋白质合成。在亨廷顿氏病模型中，误译细胞耐药且在聚谷氨酰胺聚集物清除方面存在缺陷。
In neurodegenerative diseases, including pathologies with well-known causative alleles, genetic factors that modify severity or age of onset are not entirely understood. We recently documented the unexpected prevalence of transfer RNA (tRNA) mutants in the human population, including variants that cause amino acid mis-incorporation. We hypothesized that a mistranslating tRNA will exacerbate toxicity and modify the molecular pathology of Huntington's disease-causing alleles. We characterized a tRNAPro mutant that mistranslates proline codons with alanine, and tRNASer mutants, including a tRNASerAGA G35A variant with a phenylalanine anticodon (tRNASerAAA) found in ∼2% of the population. The tRNAPro mutant caused synthetic toxicity with a deleterious huntingtin poly-glutamine (polyQ) allele in neuronal cells. The tRNASerAAA variant showed synthetic toxicity with proteasome inhibition but did not enhance toxicity of the huntingtin allele. Cells mistranslating phenylalanine or proline codons with serine had significantly reduced rates of protein synthesis. Mistranslating cells were slow but effective in forming insoluble polyQ aggregates, defective in protein and aggregate degradation, and resistant to the neuroprotective integrated stress response inhibitor (ISRIB). Our findings identify mistranslating tRNA variants as genetic factors that slow protein aggregation kinetics, inhibit aggregate clearance, and increase drug resistance in cellular models of neurodegenerative disease. A human tRNASer variant found in 1.8% of the population directs serine mis-incorporation and inhibits protein synthesis. Mistranslating cells were drug-resistant and defective in poly-glutamine aggregate clearance in models of Huntington's disease.
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影响因子：
14.9
作者：
Chan PP;Lowe TM
通讯作者：
Lowe TM
影响因子：
64.8
作者：
GOTO, Y;NONAKA, I;HORAI, S
通讯作者：
HORAI, S
影响因子：
5.6
作者：
CRICK, FHC
通讯作者：
CRICK, FHC
DOI：
10.1073/pnas.83.16.6164
发表时间：
1986-08-01
影响因子：
11.1
作者：
DAVIS, BD;CHEN, LL;TAI, PC
通讯作者：
TAI, PC
影响因子：
4.1
作者：
Berg, Matthew D.;Giguere, Daniel J.;Brandl, Christopher J.
通讯作者：
Brandl, Christopher J.