GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex
13:30 til 15:00
BMC Seminar Thursday August 31 at 13:30 in Askja, N-132
Name: Dr. Axel Methner, Professor of Neurology, Institute of Molecular Medicine, University Medical Center Mainz, Germany
Title: GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex
Abstract: Charcot-Marie-Tooth (CMT) disease 4A is an autosomal-recessive polyneuropathy caused by mutations of ganglioside-induced differentiation-associated protein 1 (GDAP1), a putative glutathione transferase, which affects mitochondrial shape and alters cellular Ca2+ homeostasis. We found that patient-derived motoneurons and GDAP1 knockdown SH-SY5Y cells display metabolic changes characterized by glutamine dependence and fewer cytosolic lipid droplets caused by inhibition of the pyruvate dehydrogenase complex. Homozygous knockout of fly Gdap1 is lethal at the larval stage while heterozygous knockout greatly diminished climbing ability and lifespan which could be rescued by a diet rich in carnitine. Similar to patient-derived motoneurons, Gdap1 +/- flies display an altered lipid metabolism. Gene reduction of the carnitine O-palmitoyltransferase withered (whd) resulted in lethality of Gdap1 +/- flies. Together, our findings define the pathomechanism of CMT4A and identify an in vivo model of the disease amenable to pharmacological intervention.
Dr. Axel Methner, Professor of Neurology, Institute of Molecular Medicine, University Medical Center Mainz, Germany