(Sample) genotype/mutant hungtingtin; p62 +/+
Ddit4l DOWN in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Arfgef1 UP in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Anapc1 UP in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Cnr1 DOWN in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Slc17a7 DOWN in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Gpr139 DOWN in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Trdn DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
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).
Adora2a DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Kcnj13 UP in 'wild type huntingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Nptx1 DOWN in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
(Factor value) GENOTYPE/wild type huntingtin; p62 +/+
Hp1bp3 UP in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Lrrc10b DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Rab14 UP in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Derl1 UP in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Psma1 UP in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Rgs4 DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Cpne9 DOWN in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Rasgrp2 DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Gm22805 DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Npas4 DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Sqstm1 DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Akr1e1 UP in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Gpx6 DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Abi3bp DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
(Sample) genotype/mutant hungtingtin; p62 -/-
Nrn1 DOWN in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Abi3bp DOWN in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Kl UP in 'wild type huntingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Dlg1 UP in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
(Factor value) GENOTYPE/mutant hungtingtin; p62 -/-
Rab14 UP in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Rgs4 DOWN in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Trdn DOWN in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Analysis of 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
(Factor value) GENOTYPE/wild type huntingtin; p62 -/-
Cntnap3 DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Cpne9 DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Anapc1 UP in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Cd4 DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Phex DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Gm22805 DOWN in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Scn4b DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
(Sample) genotype/wild type huntingtin; p62 +/+
Ifit3 UP in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Gm10754 DOWN in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Hp1bp3 UP in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Myo3b DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Gpr139 DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
(Factor value) GENOTYPE/mutant hungtingtin; p62 +/+
Ddit4l DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Lgals3bp UP in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Gpx6 DOWN in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Coch DOWN in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Analysis of 'wild type huntingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Ttr UP in 'wild type huntingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Sqstm1 DOWN in 'wild type huntingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Itch UP in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Npas4 DOWN in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Mtif2 UP in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Scn4b DOWN in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Ryr1 DOWN in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Gm10754 DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Ryr1 DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Ube2g1 UP in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Coch DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Copa UP in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
(Sample) genotype/wild type huntingtin; p62 -/-
Analysis of 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Arfgef1 UP in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Phex DOWN in 'mutant hungtingtin; p62 +/+' vs 'wild type huntingtin; p62 +/+'
Sar1a UP in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'
Cnr1 DOWN in 'mutant hungtingtin; p62 -/-' vs 'wild type huntingtin; p62 +/+'