論文 - 詳細
| RRC ID | 59160 |
|---|---|
| 著者 | Hsieh YC, Guo C, Yalamanchili HK, Abreha M, Al-Ouran R, Li Y, Dammer EB, Lah JJ, Levey AI, Bennett DA, De Jager PL, Seyfried NT, Liu Z, Shulman JM. |
| タイトル | Tau-Mediated Disruption of the Spliceosome Triggers Cryptic RNA Splicing and Neurodegeneration in Alzheimer's Disease. |
| ジャーナル | Cell Rep |
| Abstract |
In Alzheimer's disease (AD), spliceosomal proteins with critical roles in RNA processing aberrantly aggregate and mislocalize to Tau neurofibrillary tangles. We test the hypothesis that Tau-spliceosome interactions disrupt pre-mRNA splicing in AD. In human postmortem brain with AD pathology, Tau coimmunoprecipitates with spliceosomal components. In Drosophila, pan-neuronal Tau expression triggers reductions in multiple core and U1-specific spliceosomal proteins, and genetic disruption of these factors, including SmB, U1-70K, and U1A, enhances Tau-mediated neurodegeneration. We further show that loss of function in SmB, encoding a core spliceosomal protein, causes decreased survival, progressive locomotor impairment, and neuronal loss, independent of Tau toxicity. Lastly, RNA sequencing reveals a similar profile of mRNA splicing errors in SmB mutant and Tau transgenic flies, including intron retention and non-annotated cryptic splice junctions. In human brains, we confirm cryptic splicing errors in association with neurofibrillary tangle burden. Our results implicate spliceosome disruption and the resulting transcriptome perturbation in Tau-mediated neurodegeneration in AD. |
| 巻・号 | 29(2) |
| ページ | 301-316.e10 |
| 公開日 | 2019-10-8 |
| DOI | 10.1016/j.celrep.2019.08.104 |
| PII | S2211-1247(19)31166-0 |
| PMID | 31597093 |
| PMC | PMC6919331 |
| MeSH | Alzheimer Disease / complications Alzheimer Disease / genetics* Alzheimer Disease / pathology Alzheimer Disease / physiopathology Animals Brain / metabolism Brain / pathology Brain / physiopathology Drosophila / metabolism* Drosophila Proteins / metabolism Humans Models, Biological Motor Activity Nerve Degeneration / complications Nerve Degeneration / genetics* Nerve Degeneration / physiopathology RNA Splicing / genetics* Ribonucleoproteins, Small Nuclear / metabolism Spliceosomes / metabolism* tau Proteins / metabolism* |
| IF | 8.109 |
| 引用数 | 7 |
| 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 | 97 |
| 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 | |
| ショウジョウバエ | DGRC#122076 |