title: Cell expression of GDAP1 in the nervous system and pathogenesis of Charcot-Marie-Tooth type 4A disease.
abstract: Mutations in the mitochondrial protein GDAP1 are the cause of Charcot-Marie-Tooth type 4A disease (CMT4A), a severe form of peripheral neuropathy associated with either demyelinating, axonal or intermediate phenotypes. GDAP1 is located in the outer mitochondrial membrane and it seems that may be related with the mitochondrial network dynamics. We are interested to define cell expression in the nervous system and the effect of mutations in mitochondrial morphology and pathogenesis of the disease. We investigated GDAP1 expression in the nervous system and dorsal root ganglia (DRG) neuron cultures. GDAP1 is expressed in motor and sensory neurons of the spinal cord and other large neurons such as cerebellar Purkinje neurons, hippocampal pyramidal neurons, mitral neurons of the olfactory bulb and cortical pyramidal neurons. The lack of GDAP1 staining in the white matter and nerve roots suggested that glial cells do not express GDAP1. In DRG cultures satellite cells and Schwann cells were GDAP1-negative. Overexpression of GDAP1-induced fragmentation of mitochondria suggesting a role of GDAP1 in the fission pathway of the mitochondrial dynamics. Missense mutations showed two different patterns: most of them induced mitochondrial fragmentation but the T157P mutation showed an aggregation pattern. Whereas null mutations of GDAP1 should be associated with loss of function of the protein, missense mutations may act through different pathogenic mechanisms including a dominant-negative effect, suggesting that different molecular mechanisms may underlay the pathogenesis of CMT4A.
authors.affiliation: Department of Genomics and Proteomics, Instituto de Biomedicina, CSIC, Valencia, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Pedrola
authors.forename: Antonio
authors.initials: A
authors.lastname: Espert
authors.forename: Teresa
authors.initials: T
authors.lastname: Valdés-Sánchez
authors.forename: Maribel
authors.initials: M
authors.lastname: Sánchez-Piris
authors.forename: Erich E
authors.initials: EE
authors.lastname: Sirkowski
authors.forename: Steven S
authors.initials: SS
authors.lastname: Scherer
authors.forename: Isabel
authors.initials: I
authors.lastname: Fariñas
authors.forename: Francesc
authors.initials: F
authors.lastname: Palau
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019556:COS Cells; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000145:classification / Q000209:etiology*; D002522:Chlorocebus aethiops; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D007395:Interneurons / Q000378:metabolism; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009420:Nervous System / Q000166:cytology* / Q000378:metabolism*; D009475:Neurons, Afferent / Q000378:metabolism; D011689:Purkinje Cells / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism; D051381:Rats; D013116:Spinal Cord / Q000378:metabolism
chemical_list: C118663:GDAP protein; D009419:Nerve Tissue Proteins