Comparative study of isolated and in-situ mitochondria from Hdh Knock-in (CAG150) Huntington’s disease mice

• Type: National Conference Proceedings Book
• Date: 2005

Authors

Jorge M.A. Oliveira (Author) FFUP; Jekabsons M (Author) Other; Chen S (Author) Other; Riley R (Author) Other; Lin A (Author) Other; Ellerby LM (Author) Other; Rego AC (Author) Other; Nicholls DG (Author) Other

Publisher

Sinapse

Conference National

9a Reunião da Sociedade Portuguesa de Neurociências

Grande Hotel do Luso, Portugal, 19 a 20 de maio de 2005

Scientific classification

FOS: Medical and Health sciences > Health sciences

CORDIS: Health sciences > Pharmacological sciences ; Health sciences > Neuroscience > Neurophysiology ; Health sciences > Neuroscience > Neurochemistry

Other information

Resumo (PT): Huntington's disease (HD), caused by mutant huntingtin (htt), is the most common inherited neurodegenerative disorder. There is currently no cure or effective treatment for this highly debilitating disorder that primarily targets the striatum. The development of animal models that accurately recapitulate HD pathology is essential for the development and testing of effective treatments. Several mouse models have been developed by different techniques many of which involve the random insertion of truncated or full-lenght forms of htt cDNA in the mouse genome. Studies conducted in mitochondria isolated from such models suggest organelle dysfunction. However, inappropriate expression of any HD transgene may lead to toxicity by mechanisms not representative of HD. In the present study, we assessed mytochondrial function using knock-in mice, which are considered the best genetic models as they differ from wild-type exclusively in the number of CAG repeats in the gene encoding htt. To further minimize genetic variability comparisons were made with wild-type littermates. No differences in maximal respiration and Ca2+ loading capacity were found between isolated forebrain mitochondria obtained from adult wild-type and homozygous or heterozygous Hdh knock-in mice. However, a decreased maximal respiratory capacity was detected in in situ mitochondria from Hdh knock-in striatal neurons. Furthermore, homozygous Hdh knock-in striatal neurons presented a marked impairment of recovery from NMDA challenge in pyruvate-based media. These results suggest mitochondrial dysfunction in Hdh knock-in mice. The fact that this was not detected in isolated forebrain mitochondria may be explained by the mixed neuronal population of the forebrain that masks the selective striatal pathology of HD. Additionally, isolated mitochondria are no longer in contact with the components of an intact neuron, namely soluble cytoplasmic htt, thus reinforcing the importance of measurements performed in in-situ mitochondria. Acknowledgements: This work was supported by a grant from the HighQ Foundation and the Calouste Gulbenkian Foundation

Abstract (EN): Huntington's disease (HD), caused by mutant huntingtin (htt), is the most common inherited neurodegenerative disorder. There is currently no cure or effective treatment for this highly debilitating disorder that primarily targets the striatum. The development of animal models that accurately recapitulate HD pathology is essential for the development and testing of effective treatments. Several mouse models have been developed by different techniques many of which involve the random insertion of truncated or full-lenght forms of htt cDNA in the mouse genome. Studies conducted in mitochondria isolated from such models suggest organelle dysfunction. However, inappropriate expression of any HD transgene may lead to toxicity by mechanisms not representative of HD. In the present study, we assessed mytochondrial function using knock-in mice, which are considered the best genetic models as they differ from wild-type exclusively in the number of CAG repeats in the gene encoding htt. To further minimize genetic variability comparisons were made with wild-type littermates. No differences in maximal respiration and Ca2+ loading capacity were found between isolated forebrain mitochondria obtained from adult wild-type and homozygous or heterozygous Hdh knock-in mice. However, a decreased maximal respiratory capacity was detected in in situ mitochondria from Hdh knock-in striatal neurons. Furthermore, homozygous Hdh knock-in striatal neurons presented a marked impairment of recovery from NMDA challenge in pyruvate-based media. These results suggest mitochondrial dysfunction in Hdh knock-in mice. The fact that this was not detected in isolated forebrain mitochondria may be explained by the mixed neuronal population of the forebrain that masks the selective striatal pathology of HD. Additionally, isolated mitochondria are no longer in contact with the components of an intact neuron, namely soluble cytoplasmic htt, thus reinforcing the importance of measurements performed in in-situ mitochondria. Acknowledgements: This work was supported by a grant from the HighQ Foundation and the Calouste Gulbenkian Foundation

Language: Portuguese

Type (Professor's evaluation): Scientific