Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of cerebellum from transgenic mice with nuclear and extranuclear polyQ to investigate the role of polyQ in Huntingtons disease

ABSTRACT: To dissect the impact of nuclear and extranuclear mutant htt on the initiation and progression of disease, we generated a series of transgenic mouse lines in which nuclear localization (NLS) or nuclear export sequences (NES) have been placed N-terminal to the htt exon 1 protein carrying 144 glutamines. Our data indicate that the exon 1 mutant protein is present in the nucleus as part of an oligomeric or aggregation complex. Increasing the concentration of the mutant transprotein in the nucleus is sufficient for, and dramatically accelerates the onset and progression of behavioral phenotypes. Furthermore, nuclear exon 1 mutant protein is sufficient to induce cytoplasmic neurodegeneration and transcriptional dysregulation. However, our data suggests that cytoplasmic mutant exon 1 htt, if present, contributes to disease progression.

Five lines of transgenic mice and normal littermate controls were compared using Affymetrix MG-U74Av2 A arrays to examine gene expression in cerebellum. Each line had 3 or 4 replicates. Profiles were made at the first age that rotorod deficits could be detected. Some lines were also profiled at a later age when neurological impairment was more pronounced.

ORGANISM(S): Mus musculus

SUBMITTER: Andrew Strand

PROVIDER: E-GEOD-3248 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Contribution of nuclear and extranuclear polyQ to neurological phenotypes in mouse models of Huntington's disease.

Benn Caroline L CL Landles Christian C Li He H Strand Andrew D AD Woodman Ben B Sathasivam Kirupa K Li Shi-Hua SH Ghazi-Noori Shabnam S Hockly Emma E Faruque Syed M N N SM Cha Jang-Ho J JH Sharpe Paul T PT Olson James M JM Li Xiao-Jiang XJ Bates Gillian P GP

Human molecular genetics 20050923 20

In postmortem Huntington's disease brains, mutant htt is present in both nuclear and cytoplasmic compartments. To dissect the impact of nuclear and extranuclear mutant htt on the initiation and progression of disease, we generated a series of transgenic mouse lines in which nuclear localization or nuclear export signal sequences have been placed N-terminal to the htt exon 1 protein carrying 144 glutamines. Our data indicate that the exon 1 mutant protein is present in the nucleus as part of an o ...[more]

PMID: 16183657

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Project description:Huntington's disease (HD) is a dominantly inherited genetic disease caused by mutant huntingtin (htt) protein with expanded polyglutamine tracts. A neuropathological hallmark of HD is the presence of neuronal inclusions of mutant htt. p62 is an important regulatory protein in selective autophagy, a process by which aggregated proteins are degraded, and it is associated with several neurodegenerative disorders including HD. Here we investigated the effect of p62 depletion in three HD model mice: R6/2, HD190QG and HD120QG mice. We found that loss of p62 in these models led to longer lifespans and reduced nuclear inclusions, although cytoplasmic inclusions increased with polyglutamine length. In mouse embryonic fibroblasts (MEFs) with or without p62, mutant htt with a nuclear localization signal (NLS) showed no difference in nuclear inclusion between the two MEF types. In the case of mutant htt without NLS, however, p62 depletion increased cytoplasmic inclusions. Furthermore, to examine the effect of impaired autophagy in HD model mice, we crossed R6/2 mice with Atg5 conditional knockout mice. These mice also showed decreased nuclear inclusions and increased cytoplasmic inclusions, similar to HD mice lacking p62. These data suggest that the genetic ablation of p62 in HD model mice enhances cytoplasmic inclusion formation by interrupting autophagic clearance of polyQ inclusions. This reduces polyQ nuclear influx and paradoxically ameliorates disease phenotypes by decreasing toxic nuclear inclusions. Gene expression profiles were analyzed to examine the effects of p62 depletion in mouse with or without mutant huntingtin exon 1 To examine the effect of p62 depletion on the transcriptome of Huntington's disease model mice, we crossed p62 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 p62 knockout (HD_p62KO), HD mice with normal p62 (HD_p62WT), non-HD-transgenic mice with p62 knockout (NT_p62KO), and non-HD-transgenic mice with normal p62 (NT_p62WT).

Dataset Information

Transcription profiling of cerebellum from transgenic mice with nuclear and extranuclear polyQ to investigate the role of polyQ in Huntingtons disease

Publications

Contribution of nuclear and extranuclear polyQ to neurological phenotypes in mouse models of Huntington's disease.

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