Dopamine determines the vulnerability of striatal neurons to the N-terminal fragment of mutant huntingtin through the regulation of mitochondrial complex II
| Autor: | Noelle Dufour, Philippe Hantraye, Elsa Diguet, Nicole Déglon, Alexandra Benchoua, Stan Krajewski, Jean-Marc Elalouf, Yaël Trioulier, Emmanuel Brouillet, Carole Malgorn, Marie-Claude Gaillard |
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| Rok vydání: | 2008 |
| Předmět: |
Huntingtin
Dopamine Dopamine Agents Cell Culture Techniques Down-Regulation Gene Expression Nerve Tissue Proteins Striatum Biology chemistry.chemical_compound Dopamine receptor D1 Dopamine receptor D3 Genetics Huntingtin Protein medicine Animals Neurotransmitter Molecular Biology Genetics (clinical) Neurons Receptors Dopamine D2 Electron Transport Complex II Dopaminergic Nuclear Proteins Articles General Medicine Corpus Striatum Rats Cell biology Dopamine D2 Receptor Antagonists Protein Subunits nervous system Biochemistry chemistry Mutant Proteins medicine.drug |
| Zdroj: | Human Molecular Genetics |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | In neurodegenerative disorders associated with primary or secondary mitochondrial defects such as Huntington's disease (HD), cells of the striatum are particularly vulnerable to cell death, although the mechanisms by which this cell death is induced are unclear. Dopamine, found in high concentrations in the striatum, may play a role in striatal cell death. We show that in primary striatal cultures, dopamine increases the toxicity of an N-terminal fragment of mutated huntingtin (Htt-171-82Q). Mitochondrial complex II protein (mCII) levels are reduced in HD striatum, indicating that this protein may be important for dopamine-mediated striatal cell death. We found that dopamine enhances the toxicity of the selective mCII inhibitor, 3-nitropropionic acid. We also demonstrated that dopamine doses that are insufficient to produce cell loss regulate mCII expression at the mRNA, protein and catalytic activity level. We also show that dopamine-induced down-regulation of mCII levels can be blocked by several dopamine D2 receptor antagonists. Sustained overexpression of mCII subunits using lentiviral vectors abrogated the effects of dopamine, both by high dopamine concentrations alone and neuronal death induced by low dopamine concentrations together with Htt-171-82Q. This novel pathway links dopamine signaling and regulation of mCII activity and could play a key role in oxidative energy metabolism and explain the vulnerability of the striatum in neurodegenerative diseases. |
| Databáze: | OpenAIRE |
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