HMG-CoA reductase inhibition causes neurite loss by interfering with geranylgeranylpyrophosphate synthesis |
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Authors: | Schulz Joachim G Bösel Julian Stoeckel Magali Megow Dirk Dirnagl Ulrich Endres Matthias |
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Affiliation: | Department of Experimental Neurology, Charité, Humboldt University, Berlin, Germany. joachim.schulz@med.kuleuven.ac.be |
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Abstract: | 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. |
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Keywords: | cholesterol geranylgeranylpyrophosphate hydroxymethylglutaryl coenzyme A reductase neurite outgrowth PC12 cells |
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