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Huntington disease iPSCs show early molecular changes in intracellular signaling, the expression of oxidative stress proteins and the p53 pathway.

Szlachcic WJ, Switonski PM, Krzyzosiak WJ, Figlerowicz M, Figiel M - Dis Model Mech (2015)

Bottom Line: Several molecular and developmental effects of HD have been identified using neural stem cells (NSCs) and differentiated cells, such as neurons and astrocytes.Surprisingly, we found that a number of changes affecting cellular processes in HD were also present in undifferentiated pluripotent HD iPSCs, including the dysregulation of the MAPK and Wnt signaling pathways and the dysregulation of the expression of genes related to oxidative stress, such as Sod1.Interestingly, a common protein interactor of the huntingtin protein and the proteins in the above pathways is p53, and the expression of p53 was dysregulated in HD YAC128 iPSCs and human HD iPSCs.

View Article: PubMed Central - PubMed

Affiliation: Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, Poznań 61-704, Poland.

No MeSH data available.


Related in: MedlinePlus

The levels of p53 (Trp53) mRNA and protein were altered in HD iPSCs. (A) Real-time qPCR analysis revealed the increased expression of p53 mRNA in HD YAC128 iPSCs. (B,C) Western blotting and densitometric analysis revealed that p53 protein levels were decreased in the HD YAC128 iPSCs. * indicates the YAC128/Oct-eGFP lines. (D) p53 protein levels were decreased in human juvenile HD iPSC lines but not in human HD 71 iPSC lines (P=0.0285, 1-way ANOVA; P<0.05, Bonferroni post-test).
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DMM019406F8: The levels of p53 (Trp53) mRNA and protein were altered in HD iPSCs. (A) Real-time qPCR analysis revealed the increased expression of p53 mRNA in HD YAC128 iPSCs. (B,C) Western blotting and densitometric analysis revealed that p53 protein levels were decreased in the HD YAC128 iPSCs. * indicates the YAC128/Oct-eGFP lines. (D) p53 protein levels were decreased in human juvenile HD iPSC lines but not in human HD 71 iPSC lines (P=0.0285, 1-way ANOVA; P<0.05, Bonferroni post-test).

Mentions: In our search for molecular pathways that were dysregulated in the YAC128 iPSCs, we detected altered activation profiles of the ERK and Wnt pathways and the accumulation of mutant huntingtin and SOD1. p53 is a pleiotropic molecule that binds huntingtin (Steffan et al., 2000), interacts with ERK and Wnt pathways and plays a role in oxidative stress. Data mining using the STRING 9.1 database (Franceschini et al., 2013) revealed that all molecules with dysregulated processes in HD YAC128 iPSCs interact with p53 (Fig. 7). In our studies, investigation of the level of p53 expression revealed the induction of the expression of Trp53 mRNA (Fig. 8A); however, the level of the protein was strongly reduced in the HD YAC128 iPSCs (Fig. 8B,C). Interestingly, in human iPSCs, we observed a strong (tenfold) decrease in p53 protein in the juvenile HD 109 CAG line (Fig. 8D). However, this effect was absent in the HD 71 CAG line (P=0.0285, 1-way ANOVA; P<0.05, Bonferroni post-test).Fig. 7.


Huntington disease iPSCs show early molecular changes in intracellular signaling, the expression of oxidative stress proteins and the p53 pathway.

Szlachcic WJ, Switonski PM, Krzyzosiak WJ, Figlerowicz M, Figiel M - Dis Model Mech (2015)

The levels of p53 (Trp53) mRNA and protein were altered in HD iPSCs. (A) Real-time qPCR analysis revealed the increased expression of p53 mRNA in HD YAC128 iPSCs. (B,C) Western blotting and densitometric analysis revealed that p53 protein levels were decreased in the HD YAC128 iPSCs. * indicates the YAC128/Oct-eGFP lines. (D) p53 protein levels were decreased in human juvenile HD iPSC lines but not in human HD 71 iPSC lines (P=0.0285, 1-way ANOVA; P<0.05, Bonferroni post-test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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DMM019406F8: The levels of p53 (Trp53) mRNA and protein were altered in HD iPSCs. (A) Real-time qPCR analysis revealed the increased expression of p53 mRNA in HD YAC128 iPSCs. (B,C) Western blotting and densitometric analysis revealed that p53 protein levels were decreased in the HD YAC128 iPSCs. * indicates the YAC128/Oct-eGFP lines. (D) p53 protein levels were decreased in human juvenile HD iPSC lines but not in human HD 71 iPSC lines (P=0.0285, 1-way ANOVA; P<0.05, Bonferroni post-test).
Mentions: In our search for molecular pathways that were dysregulated in the YAC128 iPSCs, we detected altered activation profiles of the ERK and Wnt pathways and the accumulation of mutant huntingtin and SOD1. p53 is a pleiotropic molecule that binds huntingtin (Steffan et al., 2000), interacts with ERK and Wnt pathways and plays a role in oxidative stress. Data mining using the STRING 9.1 database (Franceschini et al., 2013) revealed that all molecules with dysregulated processes in HD YAC128 iPSCs interact with p53 (Fig. 7). In our studies, investigation of the level of p53 expression revealed the induction of the expression of Trp53 mRNA (Fig. 8A); however, the level of the protein was strongly reduced in the HD YAC128 iPSCs (Fig. 8B,C). Interestingly, in human iPSCs, we observed a strong (tenfold) decrease in p53 protein in the juvenile HD 109 CAG line (Fig. 8D). However, this effect was absent in the HD 71 CAG line (P=0.0285, 1-way ANOVA; P<0.05, Bonferroni post-test).Fig. 7.

Bottom Line: Several molecular and developmental effects of HD have been identified using neural stem cells (NSCs) and differentiated cells, such as neurons and astrocytes.Surprisingly, we found that a number of changes affecting cellular processes in HD were also present in undifferentiated pluripotent HD iPSCs, including the dysregulation of the MAPK and Wnt signaling pathways and the dysregulation of the expression of genes related to oxidative stress, such as Sod1.Interestingly, a common protein interactor of the huntingtin protein and the proteins in the above pathways is p53, and the expression of p53 was dysregulated in HD YAC128 iPSCs and human HD iPSCs.

View Article: PubMed Central - PubMed

Affiliation: Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, Poznań 61-704, Poland.

No MeSH data available.


Related in: MedlinePlus