Salazar Dominique A, Butler Victoria J, Argouarch Andrea R, Hsu Tsung-Yuan, Mason Amanda, Nakamura Ayumi, McCurdy Helen, Cox David, Ng Rachel, Pan Gloria, Seeley William W, Miller Bruce L, Kao Aimee W
Department of Neurology, University of California at San Francisco, San Francisco, California 94158, and.
Gladstone Institutes of Neurological Disease, San Francisco, California 94148.
J Neurosci. 2015 Jun 24;35(25):9315-28. doi: 10.1523/JNEUROSCI.4808-14.2015.
Mutations in the human progranulin gene resulting in protein haploinsufficiency cause frontotemporal lobar degeneration with TDP-43 inclusions. Although progress has been made in understanding the normal functions of progranulin and TDP-43, the molecular interactions between these proteins remain unclear. Progranulin is proteolytically processed into granulins, but the role of granulins in the pathogenesis of neurodegenerative disease is unknown. We used a Caenorhabditis elegans model of neuronal TDP-43 proteinopathy to specifically interrogate the contribution of granulins to the neurodegenerative process. Complete loss of the progranulin gene did not worsen TDP-43 toxicity, whereas progranulin heterozygosity did. Interestingly, expression of individual granulins alone had little effect on behavior. In contrast, when granulins were coexpressed with TDP-43, they exacerbated its toxicity in a variety of behaviors including motor coordination. These same granulins increased TDP-43 levels via a post-translational mechanism. We further found that in human neurodegenerative disease subjects, granulin fragments accumulated specifically in diseased regions of brain. To our knowledge, this is the first demonstration of a toxic role for granulin fragments in a neurodegenerative disease model. These studies suggest that presence of cleaved granulins, rather than or in addition to loss of full-length progranulin, may contribute to disease in TDP-43 proteinopathies.
人类原颗粒蛋白基因发生突变导致蛋白质单倍剂量不足，会引发伴有TDP-43包涵体的额颞叶痴呆。尽管在了解原颗粒蛋白和TDP-43的正常功能方面已取得进展，但这些蛋白质之间的分子相互作用仍不清楚。原颗粒蛋白经蛋白水解加工成颗粒蛋白，但颗粒蛋白在神经退行性疾病发病机制中的作用尚不清楚。我们利用线虫神经元TDP-43蛋白病模型，专门探究颗粒蛋白对神经退行性过程的影响。原颗粒蛋白基因完全缺失并不会加重TDP-43的毒性，而原颗粒蛋白杂合性缺失则会加重其毒性。有趣的是，单独表达单个颗粒蛋白对行为几乎没有影响。相比之下，当颗粒蛋白与TDP-43共表达时，它们会在包括运动协调在内的多种行为中加剧TDP-43的毒性。这些相同的颗粒蛋白通过翻译后机制提高了TDP-43的水平。我们进一步发现，在人类神经退行性疾病患者中，颗粒蛋白片段特异性地在脑病变区域积累。据我们所知，这是首次在神经退行性疾病模型中证明颗粒蛋白片段具有毒性作用。这些研究表明，切割后的颗粒蛋白的存在，而非全长原颗粒蛋白的缺失，或者除了全长原颗粒蛋白缺失之外，可能在TDP-43蛋白病的发病过程中发挥作用。
