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	Axel Niemann, Marcel Ruegg, Veronica La Padula, Angelo Schenone, Ueli Suter
Journal	The Journal of cell biology (J Cell Biol) Vol. 170 Issue 7 Pg. 1067-78 (Sep 26 2005) ISSN: 0021-9525 [Print] United States
PMID	16172208 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	GDAP protein Membrane Proteins Membrane Transport Proteins Microtubule-Associated Proteins Mitochondrial Membrane Transport Proteins Mitochondrial Proteins Nerve Tissue Proteins GTP Phosphohydrolases MFN2 protein, human Mfn1 protein, human DNM1L protein, human Dynamins
Topics	Animals Cells, Cultured Charcot-Marie-Tooth Disease (etiology, genetics, metabolism) Dynamins GTP Phosphohydrolases (metabolism, pharmacology) Gene Expression Regulation Humans Intracellular Membranes (chemistry) Membrane Proteins (metabolism) Membrane Transport Proteins (metabolism) Mice Microtubule-Associated Proteins (pharmacology) Mitochondria (chemistry, pathology, physiology) Mitochondrial Membrane Transport Proteins (genetics, physiology) Mitochondrial Proteins (metabolism, pharmacology) Models, Biological Mutation Nerve Tissue Proteins (analysis, genetics, physiology) Neurons (cytology, metabolism) Rats Schwann Cells (cytology, metabolism)

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