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

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.

Mitochondria dynamism: of shape, transport and cell migration

“…1). Besides FIS1 in mammals [30], MTP18 [31], endophilin B1 [32] and GDAP1 [33], other new players have also been recently identified, such as MFF, MiD49, and MiD51 (or MIeF1), all required for cytoplasmatically-localized DRP1 activation and for its recruitment to mitochondria fission sites [34,35]. It has been shown that MiD49/MiD51 also recruit DRP1 to the mitochondria in the absence of hFIS1 and/or MFF [36].…”

Mitochondrial outer-membrane permeabilization and remodelling in apoptosis

“…Another protein, Mtp-18, induces Drp-1-dependent mitochondrial fission (Tondera et al, 2004(Tondera et al, , 2005. Finally, over-expression of Gdap-1, a protein of the MOM, induces mitochondrial fission, whereas its loss of function induces mitochondrial elongation (Niemann et al, 2005;Pedrola et al, 2005).…”

The Dynamics of the Mitochondrial Organelle as a Potential Therapeutic Target

“…A large subset of patients with CMT type 2A (CMT2A) were found to have a mutations in the mitofusin 2 (MFN2) gene, primarily localized to the GTPase domain, 70 and typically exhibit earlier onset and increased severity compared with CMT2 patients without MFN2 mutations. 71 In addition, several mutations leading to the CMT type 4A disease phenotype were traced to the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene, 72 a regulator of mitochondrial fission. 73 Although the precise cellular physiologic mechanism(s) underlying the disease pathology is still poorly understood, disease-associated mutations in MFN2 and GDAP1 lead to abnormal formation of mitochondrial networks in peripheral nerve axons and myelin sheaths.…”