Protein aggregates that result in inclusion formation are a pathological hallmark common to many neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease and Huntington's disease. Under conditions of cellular stress, activation of the heat shock response (HSR) results in an increase in the levels of molecular chaperones and is a first line of cellular defence against inclusion formation. It remains to be established whether neurodegenerative disease-associated proteins and inclusions are themselves capable of inducing an HSR in neuronal cells. To address this, we generated a neuroblastoma cell line that expresses a fluorescent reporter protein under conditions of heat shock transcription factor 1 (HSF1)-mediated HSR induction. We show that the HSR is not induced by exogenous treatment with aggregated forms of recombinant α-synuclein or the G93A mutant of superoxide dismutase-1 (SOD1^G93A) nor intracellular expression of SOD1^G93A or a pathogenic form of polyglutamine-expanded huntingtin (Htt^72Q). These results suggest that pathogenic proteins evade detection or impair induction of the HSR in neuronal cells. A failure of protein aggregation to induce an HSR might contribute to the development of inclusion pathology in neurodegenerative diseases.

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导致包涵体形成的蛋白质聚集体是许多神经退行性疾病（包括肌萎缩性侧索硬化症，帕金森氏病和亨廷顿氏病）共有的病理标志。在细胞应激条件下，热休克反应（HSR）的激活导致分子伴侣水平的增加，并且是细胞对抗内含物形成的第一道防线。与神经退行性疾病相关的蛋白质和内含物本身是否能够在神经元细胞中诱导HSR，还有待确定。为了解决这个问题，我们生成了神经母细胞瘤细胞系，该细胞系在热休克转录因子1（HSF1）介导的HSR诱导下表达荧光报道蛋白。^G93A）或SOD1的细胞内表达^G93A或致病性形式的聚谷氨酰胺扩展的亨廷顿蛋白（Htt ^72Q）。这些结果表明，致病蛋白逃避了神经元细胞中HSR的检测或损害。蛋白质聚集未能诱导HSR可能有助于神经退行性疾病中包涵体病理的发展。

本文与论文的第一作者进行了第一人称访谈。