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| Status |
Public on Feb 12, 2017 |
| Title |
FUS/TLS acts as an aggregation-dependent modifier of polyglutamine disease model mice (I) |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
FUS/TLS is an RNA/DNA-binding protein associated with neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Previously, we found that a prion-like domain in the N-terminus of FUS/TLS mediates co-aggregation between FUS/TLS and mutant huntingtin, the gene product of Huntington's disease (HD). Here, we show that heterozygous knockout of FUS/TLS worsened the phenotypes of model mice of Huntington's disease (HD) but not spinal and bulbar muscular atrophy (SBMA). This difference was correlated with the degree of pathological association between disease proteins and FUS/TLS. Co-aggregation between FUS/TLS and mutant huntingtin resulted in the depletion of free FUS/TLS protein in HD mice that was detected as a monomer in SDS-PAGE analysis. Recently, we found that FUS/TLS paralogs, TAF15 and EWS, were up-regulated in homozygous FUS/TLS knockout mice. These two proteins were up-regulated in both HD and FUS/TLS heterozygote mice, and were further elevated in HD-TLS+/- double mutant mice, consistent with the functional impairment of FUS/TLS. These results suggest that FUS/TLS sequestration by co-aggregation is a rate-limiting factor of disease phenotypes of HD and that inclusions may have an adverse aspect, rather than being simply benign or protective. In addition, our results highlight inclusions as repositories of potential modifiers of neurodegeneration.
Gene expression profiles were analyzed to examine the effects of FUS/TLS heterozygosity in mouse with or without the transgene of mutant huntingtin exon 1.
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| Overall design |
To examine the effect of FUS/TLS heterozygosity on the transcriptome of Huntington's disease model mice, we crossed FUS/TLS heterozygous knockout mice with HD model mice. We extracted total RNA from the striatum of these mice at 8 weeks and used for a microaaray analysis. The samples are HD transgenic mice with FUS/TLS heterozygosity (HD_TLS+/-), HD mice with normal FUS/TLS (HD_TLS+/+), non-HD-transgenic mice with FUS/TLS heterozygosity (NT_TLS+/-), and non-HD-transgenic mice with normal FUS/TLS (NT_TLS+/+).
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| Contributor(s) |
Kino Y, Nukina N |
| Citation(s) |
27739513 |
| Submission date |
Apr 07, 2016 |
| Last update date |
Mar 06, 2018 |
| Contact name |
Yoshihiro Kino |
| E-mail(s) |
kino@my-pharm.ac.jp
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| Organization name |
Meiji Pharmaceutical University
|
| Street address |
2-522-1 Noshio, Kiyose
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| City |
Tokyo |
| ZIP/Postal code |
204-8588 |
| Country |
Japan |
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| Platforms (1) |
| GPL6096 |
[MoEx-1_0-st] Affymetrix Mouse Exon 1.0 ST Array [transcript (gene) version] |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE80109 |
FUS/TLS acts as an aggregation-dependent modifier of polyglutamine disease model mice |
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| Relations |
| BioProject |
PRJNA317612 |
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