Transcription deregulation and mitochondria crosstalk in Huntington's disease

Abstract

Event Abstract Back to Event Transcription deregulation and mitochondria crosstalk in Huntington's disease Tatiana Rosado-Rosenstock1, Mario Noro-Laco1, 2*, Oliveira C. R1, 2 and Ana Cristina-Rego1, 2 1 University of Coimbra, Center for Neuroscience and Cell Biology, Portugal 2 University of Coimbra, Faculty of Medicine, Portugal Huntington’s Disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by neuronal loss in the striatum. HD is caused by an expansion of the trinucleotide CAG in the HD gene, responsible for the translation of mutant huntingtin (mhtt) with a long polyglutamine stretch in its N-terminal. As a consequence, mhtt interacts with several other proteins, such as caspase 3 and glyceraldehyde 3-phosphate dehydrogenase. Since mhtt can also interact with many transcriptional factors and because some of the mechanisms related to the neurodegeneration observed in HD are associated with transcriptional deregulation and mitochondrial dysfunction, the objective of this work is to investigate changes in expression of transcription factors and nuclear-encoded candidate proteins that may influence mitochondrial function in a cellular model of HD. For this purpose we used striatal cells derived from HD knock-in mice expressing full-length mutant huntingtin with 111 glutamines (Q111) versus striatal cells expressing normal huntingtin (Q7). No significant changes were observed in total levels of CBP, p65 and p53 between both cell lines. However, we determined a significant decrease in the expression of CBP and p53 in nuclear fractions isolated from Q111 compared to Q7 cells. Moreover, we observed a significant decrease in total CREB levels in Q111 cells, but no changes were observed in the ratio P-CREB/CREB. Additionally, there was a significant decrease in the mitochondrial levels of prohibitin-1 in Q111, in comparison to Q7 cells. Since prohibitin is a nuclear-encoded protein localized in the inner mitochondrial membrane that seems to act as chaperone for the stabilization of mitochondrial proteins preventing their misfolding, our data suggest that full-length mhtt affects not only the transcription of nuclear encoded proteins, including mitochondrial proteins, but also mitochondrial protein stabilization, which may underlie changes in mitochondrial function. These alterations in transcription and in the overall quality of the protein content inside the cell could trigger cell death. However, levels of pro-apoptotic protein, Bax, were lower in mitochondrial extracts of Q111 cell line. These data corroborate our results from brain mitochondria extracted from YAC mice expressing full-length human mHtt with 128 glutamines (Q128). The YAC 128 mitochondrial extracts have shown to be more enriched in anti-apoptotic proteins Bcl-2 and displayed higher levels of cytochrome C and AIF. Altogether, our results indicate the existence of transcriptional deregulation and protein destabilization under mHtt expression, although the prolonged exposure to this pathological protein might trigger compensatory mechanisms, which would account for the increased resilience to cell death activation. Conference: 11th Meeting of the Portuguese Society for Neuroscience, Braga, Portugal, 4 Jun - 6 Jun, 2009. Presentation Type: Oral Presentation Topic: Symposium 3 – Neurodegenerative Disorders Citation: Rosado-Rosenstock T, Noro-Laco M, R OC and Cristina-Rego A (2009). Transcription deregulation and mitochondria crosstalk in Huntington's disease. Front. Neurosci. Conference Abstract: 11th Meeting of the Portuguese Society for Neuroscience. doi: 10.3389/conf.neuro.01.2009.11.010 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 05 Aug 2009; Published Online: 05 Aug 2009. * Correspondence: Mario Noro-Laco, University of Coimbra, Center for Neuroscience and Cell Biology, Alicante, Portugal, Portugal.mariolnl@cnc.cj.uc.pt Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Tatiana Rosado-Rosenstock Mario Noro-Laco Oliveira C R Ana Cristina-Rego Google Tatiana Rosado-Rosenstock Mario Noro-Laco Oliveira C R Ana Cristina-Rego Google Scholar Tatiana Rosado-Rosenstock Mario Noro-Laco Oliveira C R Ana Cristina-Rego PubMed Tatiana Rosado-Rosenstock Mario Noro-Laco Oliveira C R Ana Cristina-Rego Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.