Trax: A versatile signaling protein plays key roles in synaptic plasticity and DNA repair

Chern, Yijuang; Chien, Ting Yi; Fu, Xin; Shah, Anshul; Abel, Ted; Baraban, Jay M.

doi:10.1016/j.nlm.2018.07.003

Cited by 8 publications

(4 citation statements)

References 41 publications

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“…In addition to its well-known role in mediating DNA repair, this kinase also plays a prominent role in regulating insulin signaling [6]. Thus, adiposity displayed by translin KO mice might reflect dysregulation of ATM signaling pathways [5, 47]. Second, the translin/trax complex has been shown to bind to the glucose response element of the LPK gene in rat liver extracts and cultured hepatocytes [48, 49], so it may regulate LPK transcription in a microRNA-independent fashion.…”

Section: Discussionmentioning

confidence: 99%

Deletion of translin (Tsn) induces robust adiposity and hepatic steatosis without impairing glucose tolerance

Shah

Johnson

et al. 2019

Int J Obes

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Objective: Translin knockout (KO) mice display robust adiposity. Recent studies indicate that translin and its partner protein, trax, regulate the microRNA and ATM kinase signaling pathways, both of which have been implicated in regulating metabolism. In the course of characterizing the metabolic profile of these mice, we found that they display normal glucose tolerance despite their elevated adiposity. Accordingly, we investigated why translin KO mice display this paradoxical phenotype. Methods: To help distinguish between the metabolic effects of increased adiposity and those of translin deletion per se, we compared three groups: (1) wild-type (WT), (2) translin KO mice on a standard chow diet, and (3) adiposity-matched WT mice that were placed on a high-fat diet until they matched translin KO adiposity levels. All groups were scanned to determine their body composition and tested to evaluate their glucose and insulin tolerance. Plasma, hepatic and adipose tissue samples were collected and used for histological and molecular analyses. Results: Translin KO mice show normal glucose tolerance whereas adiposity-matched WT mice, placed on a high-fat diet, do not. In addition, translin KO mice display prominent hepatic steatosis that is more severe than that of adiposity-matched WT mice. Unlike adiposity-matched WT mice, translin KO mice display three key features that have been shown to reduce susceptibility to insulin resistance: increased accumulation of subcutaneous fat, increased levels of circulating adiponectin and decreased Tnfα expression in hepatic and adipose tissue. Conclusions: The ability of translin KO mice to retain normal glucose tolerance in the face of marked adipose tissue expansion may be due to the three protective factors noted above. Further studies aimed at defining the molecular bases for this combination of protective phenotypes may yield new approaches to limit the adverse metabolic consequences of obesity.

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Section: Discussionmentioning

confidence: 99%

Deletion of translin (Tsn) induces robust adiposity and hepatic steatosis without impairing glucose tolerance

Shah

Johnson

et al. 2019

Int J Obes

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“…Translin, a nuclear protein that is phylogenetically conserved in eukaryotes, constitutes a hetero-octamer together with Translin-associated factor X (TRAX) [reviewed in 1,2].…”

Section: Introductionmentioning

confidence: 99%

Translin modulates mesenchymal cell proliferation and differentiation in mice

Ikeuchi

Imanishi

Sudo

et al. 2018

Biochemical and Biophysical Research Communications

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Translin, a highly conserved DNA/RNA binding protein that forms a hetero-octamer together with Translin-associated factor X (TRAX), possesses a broad variety of functions, including RNA processing and DNA repair. Recent studies have reported that Translin is involved in mesenchymal cell physiology. Thus, here we analyzed the intrinsic role of Translin in mesenchymal cell proliferation and differentiation. Translin-deficient E11.5 mouse embryonic fibroblasts showed enhanced growth. Translin-deficient bone marrow-derived mesenchymal stem cells showed substantial expansion in vivo and enhanced proliferation in vitro. These cells also showed enhanced osteogenic and adipocytic differentiation. Histological analyses showed adipocytic hypertrophy in various adipose tissues. Translin knockout did not affect the growth of subcutaneous white adipose tissue-derived stem cells, but enhanced adipocytic differentiation was observed in vitro. Contrary to previous reports, in vitro-fertilized Translin-null mice were not runted and exhibited normal metabolic homeostasis, indicating the fragility of these mice to environmental conditions. Together, these data suggest that Translin plays an intrinsic role in restricting mesenchymal cell proliferation and differentiation.

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“…Because TRAX is a scaffold protein that acts by interacting with different proteins of distinct functions, 35 we hypothesized that TRAX and its specific binding partner under certain pathophysiological conditions may be regulated in the same manner. Earlier studies demonstrated that the expression of A 2A R (an interacting protein of TRAX) is downregulated during HD progression in humans and mice with HD 29,36 .…”

Section: Resultsmentioning

confidence: 99%

TRAX Provides Neuroprotection for Huntington's Disease Via Modulating a Novel Subset of MicroRNAs

et al. 2022

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A BS TRACT: Background: Huntington's disease (HD) is a neurodegenerative disease caused by CAG-repeat expansions (>36) in exon 1 of HTT, which dysregulates multiple cellular machineries. Translin-associated protein X (TRAX) is a scaffold protein with diverse functions, including suppressing the microRNA (miRNA)mediated silencing by degrading pre-miRNA. To date, the role of TRAX in neurodegenerative diseases remains unknown. Objectives: We delineated the role of TRAX upregulation during HD progression. Methods: Expression of TRAX in the brains of humans and three mouse models with HD were analyzed by immunohistochemistry staining, western blot, and quantitative reverse transcription-polymerase chain reaction. Adeno-associated viruses harboring TRAX short hairpin RNA were intrastriatally injected into HD mice to downregulate TRAX. HD-like symptoms were analyzed by behavioral and biochemical assessments. The miRNAsequencing and RNA-sequencing analyses were used to identify the TRAX-regulated miRNA-messenger RNA (mRNA) axis during HD progression. The identified gene targets were validated biochemically in mouse and human striatal cells. Results: We discovered that TRAX was upregulated in the brains of HD patients and three HD mouse models. Downregulation of TRAX enhanced 83 miRNAs (including miR-330-3p, miR-496a-3p) and subsequently changed the corresponding mRNA networks critical for HD pathogenesis (eg, DARPP-32 and brain-derived neurotrophic factor). Disruption of the TRAX-mediated miRNA-mRNA axis accelerated the progression of HD-like symptoms, including the degeneration of motor function, accumulation of mHTT aggregates, and shortened neurite outgrowth. Conclusions: We demonstrated that TRAX upregulation is authentic and protective in HD. Our study provides a novel layer of regulation for HD pathogenesis and may lead to the development of new therapeutic strategies for HD.

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Trax: A versatile signaling protein plays key roles in synaptic plasticity and DNA repair

Cited by 8 publications

References 41 publications

Deletion of translin (Tsn) induces robust adiposity and hepatic steatosis without impairing glucose tolerance

Deletion of translin (Tsn) induces robust adiposity and hepatic steatosis without impairing glucose tolerance

Translin modulates mesenchymal cell proliferation and differentiation in mice

TRAX Provides Neuroprotection for Huntington's Disease Via Modulating a Novel Subset of MicroRNAs

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