GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria

Laia Pedrola; Antonio Espert; Xingyao Wu; Reyes Claramunt; Michael E Shy; Francesc Palau

doi:10.1093/hmg/ddi121

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GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria

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GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria

Laia Pedrola, Antonio Espert, Xingyao Wu, Reyes Claramunt, Michael E Shy and Francesc Palau

Human molecular genetics, Vol.14(8), pp.1087-1094

04/15/2005

DOI: 10.1093/hmg/ddi121

PMID: 15772096

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Abstract

Mutations in GDAP1, the ganglioside-induced differentiation-associated protein 1 gene, cause Charcot-Marie-Tooth (CMT) type 4A, a severe autosomal recessive form of neuropathy associated with either demyelinating or axonal phenotypes. Here, we demonstrate that GDAP1 has far greater expression in neurons than in myelinating Schwann cells. We investigated cell localization of GDAP1 in a human neuroblastoma cell line by means of transient overexpression and co-localization with organelle markers in COS-7 cells and by western blot analysis of subcell fractions with anti-GDAP1 polyclonal antibodies. We observed that GDAP1 is localized in mitochondria. We also show that C-terminal transmembrane domains are necessary for the correct localization in mitochondria; however, missense mutations do not change the mitochondrial pattern of the wild-type protein. Our findings suggest that CMT4A disease is in fact a mitochondrial neuropathy mainly involving axons and represents a disease belonging to the new category of mitochondrial disorders caused by mutations in nuclear genes. We postulate that GDAP1 may be related to the maintenance of the mitochondrial network.

Protein Structure, Tertiary

Glutathione - metabolism

Humans

Cercopithecus aethiops

Mitochondria - metabolism

Mutation, Missense

Nerve Tissue Proteins - genetics

Charcot-Marie-Tooth Disease - genetics

Animals

Nerve Tissue Proteins - biosynthesis

Neurons - metabolism

COS Cells

Charcot-Marie-Tooth Disease - metabolism

Details

Title: Subtitle: GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria
Creators: Laia Pedrola - Laboratory of Genetics and Molecular Medicine, Department of Genomics and Proteomics, Instituto de Biomedicina, CSIC, Valencia, Spain
Antonio Espert
Xingyao Wu
Reyes Claramunt
Michael E Shy
Francesc Palau
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.14(8), pp.1087-1094
Publisher: England
DOI: 10.1093/hmg/ddi121
PMID: 15772096
ISSN: 0964-6906
eISSN: 1460-2083
Grant note: R01NS4139A / NINDS NIH HHS R01NS43168-01A1 / NINDS NIH HHS
Language: English
Date published: 04/15/2005
Academic Unit: Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
Record Identifier: 9984016069602771

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