BACKGROUND Monogenic protein aggregation diseases, in addition to cell selectivity, exhibit clinical variation in the age of onset and progression, driven in part by inter-individual genetic variation. While natural genetic variants may pinpoint plastic networks amenable to intervention, the mechanisms by which they impact individual susceptibility to proteotoxicity are still largely unknown. RESULTS We have previously shown that natural variation modifies polyglutamine (polyQ) aggregation phenotypes in C. elegans muscle cells. Here, we find that a genomic locus from C. elegans wild isolate DR1350 causes two genetically separable aggregation phenotypes, without changing the basal activity of muscle proteostasis pathways known to affect polyQ aggregation. We find that the increased aggregation phenotype was due to regulatory variants in the gene encoding a conserved autophagy protein ATG-5. The atg-5 gene itself conferred dosage-dependent enhancement of aggregation, with the DR1350-derived allele behaving as hypermorph. Surprisingly, increased aggregation in animals carrying the modifier locus was accompanied by enhanced autophagy activation in response to activating treatment. Because autophagy is expected to clear, not increase, protein aggregates, we activated autophagy in three different polyQ models and found a striking tissue-dependent effect: activation of autophagy decreased polyQ aggregation in neurons and intestine, but increased it in the muscle cells. CONCLUSIONS Our data show that cryptic natural variants in genes encoding proteostasis components, although not causing detectable phenotypes in wild-type individuals, can have profound effects on aggregation-prone proteins. Clinical applications of autophagy activators for aggregation diseases may need to consider the unexpected divergent effects of autophagy in different cell types.

中文翻译：

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秀丽隐杆线虫自然遗传变异揭示了自噬对多谷氨酰胺聚集的意外细胞类型依赖性影响。


背景技术除了细胞选择性之外，单基因蛋白质聚集疾病还表现出发病年龄和进展的临床变异，部分是由个体间遗传变异驱动的。虽然自然遗传变异可能会精确定位适合干预的塑料网络，但它们影响个体对蛋白质毒性敏感性的机制仍然很大程度上未知。结果我们之前已经表明自然变异改变了秀丽隐杆线虫肌肉细胞中的聚谷氨酰胺（polyQ）聚集表型。在这里，我们发现来自秀丽隐杆线虫野生分离株 DR1350 的基因组位点导致两种遗传上可分离的聚集表型，而不改变已知影响 PolyQ 聚集的肌肉蛋白质稳态途径的基础活性。我们发现聚集表型的增加是由于编码保守自噬蛋白 ATG-5 的基因中的调控变异所致。 atg-5 基因本身具有剂量依赖性的聚集增强作用，其中 DR1350 衍生的等位基因表现为超形态。令人惊讶的是，携带修饰基因座的动物中聚集的增加伴随着响应激活治疗的自噬激活的增强。由于自噬预计会清除而不是增加蛋白质聚集体，因此我们在三种不同的 PolyQ 模型中激活自噬，并发现了惊人的组织依赖性效应：自噬的激活减少了神经元和肠道中的 PolyQ 聚集，但增加了肌肉细胞中的 PolyQ 聚集。结论我们的数据表明，编码蛋白质稳态成分的基因中隐秘的自然变异虽然不会在野生型个体中引起可检测的表型，但可能对易于聚集的蛋白质产生深远的影响。 自噬激活剂治疗聚集性疾病的临床应用可能需要考虑自噬在不同细胞类型中意想不到的不同影响。