CMT4A: Cell expression of GDAP1 in the nervous system and pathogenesis

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J Cell Mol Med. 2007 Nov 16

Cell expression of GDAP1 in the nervous system and pathogenesis of

Charcot-Marie-Tooth type 4A disease.

Pedrola L, Espert A, Valdés-Sánchez T, Sánchez-Piris M, Sirkowski

EE, Scherer SS, Fariñas I, Palau F.

Department of Genomics and Proteomics, Instituto de Biomedicina,

CSIC, Valencia, Spain.

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.