Dopamine determines the vulnerability of striatal neurons to the N-terminal fragment of mutant huntingtin through the regulation of mitochondrial complex II.
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.
Benchoua
Alexandra
A
Unité de Recherche Associée, Commissariat à l'Energie Atomique (CEA)-Centre Nationale de la Recherche Scientifique (CNRS) 2210, Service Hospitalier Frédéric Joliot, Orsay Cedex, France.
Trioulier
Yaël
Y
Diguet
Elsa
E
Malgorn
Carole
C
Gaillard
Marie-Claude
MC
Dufour
Noelle
N
Elalouf
Jean-Marc
JM
Krajewski
Stan
S
Hantraye
Philippe
P
Déglon
Nicole
N
Brouillet
Emmanuel
E
D000818:Animals; D018929:Cell Culture Techniques; D003342:Corpus Striatum / Q000187:drug effects*; D004298:Dopamine / Q000494:pharmacology*; D015259:Dopamine Agents / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D015536:Down-Regulation / Q000187:drug effects; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D000071058:Huntingtin Protein; D050505:Mutant Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000378:metabolism
D015259:Dopamine Agents; D065127:Dopamine D2 Receptor Antagonists; C086055:HTT protein, human; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D021122:Protein Subunits; D017448:Receptors, Dopamine D2; D042963:Electron Transport Complex II; D004298:Dopamine