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在成年小鼠中耗尽 Trim28 耐受性良好，并降低α-突触核蛋白和 tau 的水平。

Depleting Trim28 in adult mice is well tolerated and reduces levels of α-synuclein and tau.

机构信息

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.

Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, United States.

出版信息

Elife. 2018 Jun 4;7:e36768. doi: 10.7554/eLife.36768.

DOI:10.7554/eLife.36768
PMID:29863470
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5993537/
Abstract

Alzheimer's and Parkinson's disease are late onset neurodegenerative diseases that will require therapy over decades to mitigate the effects of disease-driving proteins such tau and α-synuclein (α-Syn). Previously we found that TRIM28 regulates the levels and toxicity of α-Syn and tau (Rousseaux et al., 2016). However, it was not clear how TRIM28 regulates α-Syn and it was not known if its chronic inhibition later in life was safe. Here, we show that TRIM28 may regulate α-Syn and tau levels via SUMOylation, and that genetic suppression of Trim28 in adult mice is compatible with life. We were surprised to see that mice lacking Trim28 in adulthood do not exhibit behavioral or pathological phenotypes, and importantly, adult reduction of TRIM28 results in a decrease of α-Syn and tau levels. These results suggest that deleterious effects from TRIM28 depletion are limited to development and that its inhibition adulthood provides a potential path for modulating α-Syn and tau levels.

摘要

阿尔茨海默病和帕金森病是两种迟发性神经退行性疾病，需要数十年的治疗来减轻tau 和 α-突触核蛋白（α-Syn）等致病蛋白的影响。此前我们发现 TRIM28 可调节 α-Syn 和 tau 的水平和毒性（Rousseaux 等人，2016）。然而，TRIM28 如何调节 α-Syn 尚不清楚，其在生命晚期的慢性抑制是否安全也不得而知。在这里，我们表明 TRIM28 可能通过 SUMOylation 来调节 α-Syn 和 tau 的水平，并且成年小鼠中 Trim28 的基因抑制与生命相容。令我们惊讶的是，成年期缺乏 Trim28 的小鼠没有表现出行为或病理表型，重要的是，成年期 TRIM28 的减少导致 α-Syn 和 tau 水平降低。这些结果表明，TRIM28 耗竭的有害影响仅限于发育，而其在成年期的抑制为调节 α-Syn 和 tau 水平提供了一个潜在途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aaf6/5993537/80edcdf1f8a6/elife-36768-fig4-figsupp3.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aaf6/5993537/c6613d0b1082/elife-36768-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aaf6/5993537/b8ba71a6cfe2/elife-36768-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aaf6/5993537/02c04e4927d1/elife-36768-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aaf6/5993537/a2e2ee7af51c/elife-36768-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aaf6/5993537/01f4f3912ada/elife-36768-fig4-figsupp1.jpg
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