Compromised mitochondrial complex II in models of Machado–Joseph disease
| Autor: | Mário N. Laço, Henry L. Paulson, Catarina R. Oliveira, A. Cristina Rego |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Genetically modified mouse
Cerebellum congenital hereditary and neonatal diseases and abnormalities Mice Transgenic Nerve Tissue Proteins Mitochondrion Biology Article Cell Line Mice medicine Animals Humans Ataxin-3 Molecular Biology Cells Cultured Cell Line Transformed Neurons Cell Death Lymphoblast HEK 293 cells Neurodegeneration Nuclear Proteins Machado-Joseph Disease Tetracycline medicine.disease Nitro Compounds Molecular biology Mitochondria Succinate dehydrogenase Repressor Proteins Disease Models Animal medicine.anatomical_structure HEK293 Cells Mitochondrial Membranes Spinocerebellar ataxia Molecular Medicine Protein aggregation Propionates Peptides Machado–Joseph disease |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1822(2):139-149 |
| ISSN: | 0925-4439 |
| DOI: | 10.1016/j.bbadis.2011.10.010 |
| Popis: | Machado–Joseph disease (MJD), also known as Spinocerebellar Ataxia type 3, is an inherited dominant autosomal neurodegenerative disorder. An expansion of Cytosine-Adenine-Guanine (CAG) repeats in the ATXN3 gene is translated as an expanded polyglutamine domain in the disease protein, ataxin-3. Selective neurodegeneration in MJD is evident in several subcortical brain regions including the cerebellum. Mitochondrial dysfunction has been proposed as a mechanism of neurodegeneration in polyglutamine disorders. In this study, we used different cell models and transgenic mice to assess the importance of mitochondria on cytotoxicity observed in MJD. Transiently transfected HEK cell lines with expanded (Q84) ataxin-3 exhibited a higher susceptibility to 3-nitropropionic acid (3-NP), an irreversible inhibitor of mitochondrial complex II. Increased susceptibility to 3-NP was also detected in stably transfected PC6-3 cells that inducibly express expanded (Q108) ataxin-3 in a tetracycline-regulated manner. Moreover, cerebellar granule cells from MJD transgenic mice were more sensitive to 3-NP inhibition than wild-type cerebellar neurons. PC6-3 (Q108) cells differentiated into a neuronal-like phenotype with nerve growth factor (NGF) exhibited a significant decrease in mitochondrial complex II activity. Mitochondria from MJD transgenic mouse model and lymphoblast cell lines derived from MJD patients also showed a trend toward reduced complex II activity. Our results suggest that mitochondrial complex II activity is moderately compromised in MJD, which may designate a common feature in polyglutamine toxicity. |
| Databáze: | OpenAIRE |
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