HMG-CoA reductase inhibition causes neurite loss by interfering with geranylgeranylpyrophosphate synthesis.
To determine whether neurite outgrowth depends upon the mevalonate pathway, we blocked mevalonate synthesis in nerve growth factor-treated PC12 cells or primary cortical neurones with atorvastatin, a 3-hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and substituted different intermediates of the mevalonate pathway. We show that HMG-CoA reductase inhibition causes a profound reduction of neurite length, neurite loss and ultimatively cell death in undifferentiated and pre-differentiated PC12 cells and also in rat primary cortical neurones. Geranylgeranylpyrophosphate, but not farnesylpyrophosphate, squalene or cholesterol, completely compensated for the lack of mevalonate. Our data indicate that, under HMG-CoA reductase inhibition, geranylgeranylpyrophosphate rather than farnesylpyrophosphate or cholesterol is critical for neurite outgrowth and/or maintenance. Loss of neurites is an early manifestation of various neurodegenerative disorders, and dysfunction of isoprenylation might play a role in their pathogenesis.
Schulz
Joachim G
JG
Department of Experimental Neurology, Charité, Humboldt University, Berlin, Germany. joachim.schulz@med.kuleuven.ac.be
Bösel
Julian
J
Stoeckel
Magali
M
Megow
Dirk
D
Dirnagl
Ulrich
U
Endres
Matthias
M
D000818:Animals; D000069059:Atorvastatin; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006538:Heptanoic Acids / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011106:Polyisoprenyl Phosphates / Q000096:biosynthesis* / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D012717:Sesquiterpenes; D013185:Squalene / Q000494:pharmacology
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D011758:Pyrroles; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate; D013185:Squalene; D002784:Cholesterol; D000069059:Atorvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid