PMID:16172208

Citation	Niemann, A, Ruegg, M, La Padula, V, Schenone, A and Suter, U (2005) Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease. J. Cell Biol. 170:1067-78
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.
Links	PubMed PMC2171517 Online version:10.1083/jcb.200507087
Keywords	Animals; Cells, Cultured; Charcot-Marie-Tooth Disease/etiology; Charcot-Marie-Tooth Disease/genetics; Charcot-Marie-Tooth Disease/metabolism; GTP Phosphohydrolases/metabolism; GTP Phosphohydrolases/pharmacology; Gene Expression Regulation; Humans; Intracellular Membranes/chemistry; Membrane Proteins/metabolism; Membrane Transport Proteins/metabolism; Mice; Microtubule-Associated Proteins/pharmacology; Mitochondria/chemistry; Mitochondria/pathology; Mitochondria/physiology; Mitochondrial Membrane Transport Proteins/genetics; Mitochondrial Membrane Transport Proteins/physiology; Mitochondrial Proteins/metabolism; Mitochondrial Proteins/pharmacology; Models, Biological; Mutation; Nerve Tissue Proteins/analysis; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/physiology; Neurons/cytology; Neurons/metabolism; Rats; Schwann Cells/cytology; Schwann Cells/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:GDAP1		GO:0000266: mitochondrial fission	ECO:0000314:		P		GDAP1 promotes mitochondrial fission: Figure 4	complete

References

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