Inhibition of mitochondrial complex II alters striatal expression of genes involved in glutamatergic and dopaminergic signaling: possible implications for Huntington's disease.
Huntington's disease (HD) is a genetic neurodegenerative disorder characterized by motor abnormalities and cognitive impairment. The irreversible succinate dehydrogenase (SD) inhibitor 3-nitropropionic acid (3NP) causes neurodegeration in the striatum resembling HD when administered to rodents or primates. Using corticostriatal brain slice preparations, we analyzed the pattern of gene expression following 3NP application utilizing cDNA microarrays. Acute 3NP treatment modulates the expression of several genes involved in dopaminergic and glutamatergic signaling in corticostriatal brain slices, and unbalances the downstream serine/threonine protein kinase and phosphatase network affecting the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). Our data provide new information about the molecular events possibly underlying neurodegeneration induced by this mitochondrial toxin.
Napolitano
Maddalena
M
Dipartimento di Medicina Sperimentale e Patologia, Università La Sapienza, Rome, Italy. maddalena.napolitano@uniroma1.it
Centonze
Diego
D
Gubellini
Paolo
P
Rossi
Silvia
S
Spiezia
Stefania
S
Bernardi
Giorgio
G
Gulino
Alberto
A
Calabresi
Paolo
P
D000818:Animals; D004298:Dopamine / Q000235:genetics* / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D018698:Glutamic Acid / Q000235:genetics* / Q000378:metabolism; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D066298:In Vitro Techniques; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009419:Nerve Tissue Proteins; D009574:Nitro Compounds; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D009574:Nitro Compounds; D010750:Phosphoproteins; D011422:Propionates; D018698:Glutamic Acid; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D017346:Protein Serine-Threonine Kinases; D010744:Phosphoric Monoester Hydrolases; C015392:3-nitropropionic acid; D004298:Dopamine