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

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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.

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An optimized microRNA backbone for effective single-copy RNAi.

Christof Fellmann, Thomas Hoffmann, Vaishali Sridhar … (2013)

Short hairpin RNA (shRNA) technology enables stable and regulated gene repression. For establishing experimentally versatile RNAi tools and minimizing toxicities, synthetic shRNAs can be embedded into endogenous microRNA contexts. However, due to our incomplete understanding of microRNA biogenesis, such "shRNAmirs" often fail to trigger potent knockdown, especially when expressed from a single genomic copy. Following recent advances in design of synthetic shRNAmir stems, here we take a systematic approach to optimize the experimental miR-30 backbone. Among several favorable features, we identify a conserved element 3' of the basal stem as critically required for optimal shRNAmir processing and implement it in an optimized backbone termed "miR-E", which strongly increases mature shRNA levels and knockdown efficacy. Existing miR-30 reagents can be easily converted to miR-E, and its combination with up-to-date design rules establishes a validated and accessible platform for generating effective single-copy shRNA libraries that will facilitate the functional annotation of the genome. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

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Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss.

Yaroslava Ruzankina, Carolina Pinzon-Guzman, Amma Asare … (2007)

Developmental abnormalities, cancer, and premature aging each have been linked to defects in the DNA damage response (DDR). Mutations in the ATR checkpoint regulator cause developmental defects in mice (pregastrulation lethality) and humans (Seckel syndrome). Here we show that eliminating ATR in adult mice leads to defects in tissue homeostasis and the rapid appearance of age-related phenotypes, such as hair graying, alopecia, kyphosis, osteoporosis, thymic involution, fibrosis, and other abnormalities. Histological and genetic analyses indicate that ATR deletion causes acute cellular loss in tissues in which continuous cell proliferation is required for maintenance. Importantly, thymic involution, alopecia, and hair graying in ATR knockout mice were associated with dramatic reductions in tissue-specific stem and progenitor cells and exhaustion of tissue renewal and homeostatic capacity. In aggregate, these studies suggest that reduced regenerative capacity in adults via deletion of a developmentally essential DDR gene is sufficient to cause the premature appearance of age-related phenotypes.

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Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity

Kevin Dalgaard, Kathrin Landgraf, Steffen Heyne … (2016)

Summary More than one-half billion people are obese, and despite progress in genetic research, much of the heritability of obesity remains enigmatic. Here, we identify a Trim28-dependent network capable of triggering obesity in a non-Mendelian, “on/off” manner. Trim28 +/D9 mutant mice exhibit a bi-modal body-weight distribution, with isogenic animals randomly emerging as either normal or obese and few intermediates. We find that the obese-“on” state is characterized by reduced expression of an imprinted gene network including Nnat, Peg3, Cdkn1c, and Plagl1 and that independent targeting of these alleles recapitulates the stochastic bi-stable disease phenotype. Adipose tissue transcriptome analyses in children indicate that humans too cluster into distinct sub-populations, stratifying according to Trim28 expression, transcriptome organization, and obesity-associated imprinted gene dysregulation. These data provide evidence of discrete polyphenism in mouse and man and thus carry important implications for complex trait genetics, evolution, and medicine. Video Abstract

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Author and article information

Contributors

Jean-Pierre Revelli

Gabriel E Vázquez-Vélez

Ji-Yoen Kim

Evelyn Craigen

Kristyn Gonzales

Jaclyn Beckinghausen

Huda Y Zoghbi:

ORCID: http://orcid.org/0000-0002-0700-3349

Susan L Ackerman: Role: Reviewing Editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 04 June 2018

Publication date Collection: 2018

Volume: 7

Electronic Location Identifier: e36768

Affiliations

[1 ]deptDepartment of Molecular and Human Genetics Baylor College of Medicine HoustonUnited States

[2 ]Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital HoustonUnited States

[3 ]deptProgram in Developmental Biology Baylor College of Medicine HoustonUnited States

[4 ]deptMedical Scientist Training Program Baylor College of Medicine HoustonUnited States

[5 ]deptDepartment of Neuroscience Baylor College of Medicine HoustonUnited States

[6 ]deptHoward Hughes Medical Institute Baylor College of Medicine HoustonUnited States

[7]Howard Hughes Medical Institute, University of California, San Diego United States

[8]Howard Hughes Medical Institute, University of California, San Diego United States

Author notes

[†]

Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, University of Ottawa, Ontario, Canada.

Author information

Maxime WC Rousseaux http://orcid.org/0000-0002-2737-6193

Huda Y Zoghbi http://orcid.org/0000-0002-0700-3349

Article

Publisher ID: 36768

DOI: 10.7554/eLife.36768

PMC ID: 5993537

PubMed ID: 29863470

SO-VID: 44acae8d-cedb-42f1-973f-8dcf6bc065ac

License:

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 19 March 2018

Date accepted : 03 June 2018

Funding

Funded by: Parkinson's Foundation;

Award ID: Stanley Fahn Junior Faculty Award (PF-JFA-1762)

Award Recipient : Maxime WC Rousseaux

Funded by: UCB Pharma;