論文 - 詳細
| RRC ID | 45638 |
|---|---|
| 著者 | Salazar DA, Butler VJ, Argouarch AR, Hsu TY, Mason A, Nakamura A, McCurdy H, Cox D, Ng R, Pan G, Seeley WW, Miller BL, Kao AW. |
| タイトル | The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels. |
| ジャーナル | J Neurosci |
| Abstract |
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. |
| 巻・号 | 35(25) |
| ページ | 9315-28 |
| 公開日 | 2015-6-24 |
| DOI | 10.1523/JNEUROSCI.4808-14.2015 |
| PII | 35/25/9315 |
| PMID | 26109656 |
| PMC | PMC4478251 |
| MeSH | Animals Animals, Genetically Modified Caenorhabditis elegans DNA-Binding Proteins / metabolism* Disease Models, Animal Humans Immunoblotting Intercellular Signaling Peptides and Proteins / metabolism* Progranulins Real-Time Polymerase Chain Reaction TDP-43 Proteinopathies / metabolism* Zebrafish Proteins / metabolism |
| IF | 5.674 |
| 引用数 | 27 |
| WOS 分野 | NEUROSCIENCES |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 13 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 線虫 | tm985 |