Zhai R Grace, Zhang Fan, Hiesinger P Robin, Cao Yu, Haueter Claire M, Bellen Hugo J
Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
Nature. 2008 Apr 17;452(7189):887-91. doi: 10.1038/nature06721. Epub 2008 Mar 16.
Neurodegeneration can be triggered by genetic or environmental factors. Although the precise cause is often unknown, many neurodegenerative diseases share common features such as protein aggregation and age dependence. Recent studies in Drosophila have uncovered protective effects of NAD synthase nicotinamide mononucleotide adenylyltransferase (NMNAT) against activity-induced neurodegeneration and injury-induced axonal degeneration. Here we show that NMNAT overexpression can also protect against spinocerebellar ataxia 1 (SCA1)-induced neurodegeneration, suggesting a general neuroprotective function of NMNAT. It protects against neurodegeneration partly through a proteasome-mediated pathway in a manner similar to heat-shock protein 70 (Hsp70). NMNAT displays chaperone function both in biochemical assays and cultured cells, and it shares significant structural similarity with known chaperones. Furthermore, it is upregulated in the brain upon overexpression of poly-glutamine expanded protein and recruited with the chaperone Hsp70 into protein aggregates. Our results implicate NMNAT as a stress-response protein that acts as a chaperone for neuronal maintenance and protection. Our studies provide an entry point for understanding how normal neurons maintain activity, and offer clues for the common mechanisms underlying different neurodegenerative conditions.
神经退行性变可由遗传或环境因素引发。尽管确切病因往往不明，但许多神经退行性疾病具有诸如蛋白质聚集和年龄依赖性等共同特征。最近在果蝇中的研究发现，烟酰胺腺嘌呤二核苷酸合酶烟酰胺单核苷酸腺苷酸转移酶（NMNAT）对活性诱导的神经退行性变和损伤诱导的轴突退行性变具有保护作用。在此，我们表明NMNAT过表达也可预防脊髓小脑共济失调1型（SCA1）诱导的神经退行性变，提示NMNAT具有普遍的神经保护功能。它部分通过蛋白酶体介导的途径预防神经退行性变，其方式类似于热休克蛋白70（Hsp70）。NMNAT在生化分析和培养细胞中均表现出伴侣功能，并且与已知伴侣蛋白具有显著的结构相似性。此外，在多聚谷氨酰胺扩展蛋白过表达时，它在大脑中上调，并与伴侣蛋白Hsp70一起被募集到蛋白质聚集体中。我们的结果表明NMNAT是一种应激反应蛋白，作为神经元维持和保护的伴侣蛋白发挥作用。我们的研究为理解正常神经元如何维持活性提供了切入点，并为不同神经退行性疾病的共同机制提供了线索。
