New Implications for CMT: Ganglioside-induced differentiation associated protein

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J Cell Biol. 2005 Sep 19

Ganglioside-induced differentiation associated protein 1 is a

regulator of the mitochondrial network: new implications for Charcot-

Marie-Tooth disease.

Niemann A, Ruegg M, La Padula V, Schenone A, Suter U.

Institute of Cell Biology, Department of Biology, Swiss Federal

Institute of Technology, ETH Honggerberg, 8093 Zurich, Switzerland.

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.