title: Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease.
abstract: Mutations in GDAP1 lead to severe forms of the peripheral motor and sensory neuropathy, Charcot-Marie-Tooth disease (CMT), which is characterized by heterogeneous phenotypes, including pronounced axonal damage and demyelination. We show that neurons and Schwann cells express ganglioside-induced differentiation associated protein 1 (GDAP1), which suggest that both cell types may contribute to the mixed features of the disease. GDAP1 is located in the mitochondrial outer membrane and regulates the mitochondrial network. Overexpression of GDAP1 induces fragmentation of mitochondria without inducing apoptosis, affecting overall mitochondrial activity, or interfering with mitochondrial fusion. The mitochondrial fusion proteins, mitofusin 1 and 2 and Drp1(K38A), can counterbalance the GDAP1-dependent fission. GDAP1-specific knockdown by RNA interference results in a tubular mitochondrial morphology. GDAP1 truncations that are found in patients who have CMT are not targeted to mitochondria and have lost mitochondrial fragmentation activity. The latter activity also is reduced strongly for disease-associated GDAP1 point mutations. Our data indicate that an exquisitely tight control of mitochondrial dynamics, regulated by GDAP1, is crucial for the proper function of myelinated peripheral nerves.
authors.affiliation: Institute of Cell Biology, Department of Biology, Swiss Federal Institute of Technology, ETH Hönggerberg, 8093 Zürich, Switzerland.
authors.forename: Axel
authors.initials: A
authors.lastname: Niemann
authors.forename: Marcel
authors.initials: M
authors.lastname: Ruegg
authors.forename: Veronica
authors.initials: V
authors.lastname: La Padula
authors.forename: Angelo
authors.initials: A
authors.lastname: Schenone
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000378:metabolism / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D007425:Intracellular Membranes / Q000737:chemistry; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000494:pharmacology; D008928:Mitochondria / Q000737:chemistry / Q000473:pathology / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism / Q000494:pharmacology; D008954:Models, Biological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D051381:Rats; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism
chemical_list: C118663:GDAP protein; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D008869:Microtubule-Associated Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C470017:Mfn1 protein, human; C110768:DNM1L protein, human; D034281:Dynamins