Divergent protein context helps explain why polyglutamine expansion diseases differ clinically and pathologically. This heterogeneity may also extend to how polyglutamine disease proteins are handled by cellular pathways of proteostasis. Studies suggest, for example, that the ubiquitin-proteasome shuttle protein Ubiquilin-2 (UBQLN2) selectively interacts with specific polyglutamine disease proteins. Here we employ cellular models, primary neurons and mouse models to investigate the potential differential regulation by UBQLN2 of two polyglutamine disease proteins, huntingtin (HTT) and ataxin-3 (ATXN3). In cells, overexpressed UBQLN2 selectively lowered levels of full-length pathogenic HTT but not of HTT exon 1 fragment or full-length ATXN3. Consistent with these results, UBQLN2 specifically reduced accumulation of aggregated mutant HTT but not mutant ATXN3 in mouse models of Huntington’s disease (HD) and spinocerebellar ataxia type 3 (SCA3), respectively. Normally a cytoplasmic protein, UBQLN2 translocated to the nuclei of neurons in HD mice but not in SCA3 mice. Remarkably, instead of reducing the accumulation of nuclear mutant ATXN3, UBQLN2 induced an accumulation of cytoplasmic ATXN3 aggregates in neurons of SCA3 mice. Together these results reveal a selective action of UBQLN2 toward polyglutamine disease proteins, indicating that polyglutamine expansion alone is insufficient to promote UBQLN2-mediated clearance of this class of disease proteins. Additional factors, including nuclear translocation of UBQLN2, may facilitate its action to clear intranuclear, aggregated disease proteins like HTT.

中文翻译：

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Ubiquilin-2 差异调节多聚谷氨酰胺疾病蛋白。

不同的蛋白质背景有助于解释为什么聚谷氨酰胺扩增疾病在临床和病理上不同。这种异质性也可能扩展到多聚谷氨酰胺疾病蛋白质如何通过蛋白质稳态的细胞途径进行处理。例如，研究表明，泛素-蛋白酶体穿梭蛋白 Ubiquilin-2 (UBQLN2) 选择性地与特定的聚谷氨酰胺疾病蛋白相互作用。在这里，我们采用细胞模型、原代神经元和小鼠模型来研究 UBQLN2 对两种聚谷氨酰胺疾病蛋白亨廷顿 (HTT) 和 ataxin-3 (ATXN3) 的潜在差异调节。在细胞中，过表达的 UBQLN2 选择性地降低了全长致病性 HTT 的水平，而不是 HTT 外显子 1 片段或全长 ATXN3 的水平。与这些结果一致，. 通常是一种细胞质蛋白，UBQLN2 易位到 HD 小鼠的神经元细胞核，但不会在 SCA3 小鼠中。值得注意的是，UBQLN2 并没有减少核突变体 ATXN3 的积累，而是诱导了 SCA3 小鼠神经元中细胞质 ATXN3 聚集体的积累。这些结果共同揭示了 UBQLN2 对聚谷氨酰胺疾病蛋白的选择性作用，表明单独的聚谷氨酰胺扩增不足以促进 UBQLN2 介导的此类疾病蛋白的清除。其他因素，包括 UBQLN2 的核易位，可能会促进其清除核内聚集的疾病蛋白（如 HTT）的作用。