Unknown,Transcriptomics,Genomics,Proteomics

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Elucidating mechanisms by which regulated expression of proteoglycans and glycosylation-related genes in the striatum contribute to Huntington disease

ABSTRACT: This laboratory focuses on the molecular mechanisms of neuropsychiatric and neurodegenerative disorders Our goal is to elucidate mechanisms by which regulated expression of proteoglycans and glycosylation-related genes contribute to neurodegenerative diseases involving the striatum. A number of studies have demonstrated that neural proteoglycans are involved structural organization of the striatum and formation of dopaminergic connections to and from the striatum. Several proteoglycans are also associated with neuronal regeneration and some have been shown to be components of filamentous inclusions found in neurodegenerative disorders. In addition, the localization and proper function of dopamine receptors, which are predominantly expressed in the striatum, are governed by N-linked glycosylation events. Huntingtonís Disease (HD), a progressive neurodegenerative disorder, results in selective degeneration of the striatum. This is caused by a mutation in the protein, huntingtin, however, the mechanisms responsible for neuronal degeneration remain unknown. Similar to the brains of HD patients, HD transgenic mice exhibit huntingtin protein aggregation and nuclear inclusions, selective degeneration of dopamine neurons in the striatum and dopamine receptor dysfunction. In this study, the gene expression patterns of HD transgenic mice were analyzed. Four groups, pre-symptomatic HD mice (6 weeks old), WT control (6 weeks), post symptomatic HD (16 weeks), and WT control (16 weeks), were hybridized and analyzed using the GLYCOv2 array. Each group was hybridized in triplicate.

ORGANISM(S): Mus musculus

SUBMITTER: Steven Head

PROVIDER: E-GEOD-27588 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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).

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Elucidating mechanisms by which regulated expression of proteoglycans and glycosylation-related genes in the striatum contribute to Huntington disease

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