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Fission and disease

Proper regulation of mitochondrial fusion and fission is required for both neurons and Schwann cells, report Niemann et al. on page 1067.

Charcot-Marie-Tooth disease (CMT) is subdivided into axonal or demyelinating phenotypes, depending on whether the neurons or the myelinating Schwann cells are most affected. However, mutations in a single gene, GDAP1, can cause both phenotypes, muddying the distinction.

Niemann et al. found that GDAP1 is localized to the outer membrane of mitochondria. Overexpression of wild-type GDAP1 caused excessive fragmentation of mitochondria, whereas knock-down of GDAP1 expression resulted in long tubular mitochondria. Disease-causing mutations also impaired mitochondrial fission. However, mitochondrial physiology was not obviously disrupted in the presence of excess GDAP1 or GDAP1 mutations, leaving open the question of why the mutations induce degeneration.

GDAP1 is not the first protein involved in mitochondrial dynamics to be associated with CMT. Mutations in Mfn2, a protein required for mitochondrial fusion, is found in some patients with axonal CMT, but again, what causes the degeneration is unclear. Nor is it clear why Mfn2 primarily results in neuronal damage, whereas GDAP1 affects both neurons and Schwann cells. To find out, Niemann et al. are using conditional knock outs to determine whether neurons are most sensitive to a loss of GDAP1 activity or whether myelinating Schwann cells are the primary targets of the mutations.

Rabiya S. Tuma

rabiya{at}nasw.org

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Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease

Axel Niemann, Marcel Ruegg, Veronica La Padula, Angelo Schenone, and Ueli Suter
J. Cell Biol. 2005 170: 1067-1078. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF, 334K) Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Tuma, R. S. Search for Related Content PubMed Articles by Tuma, R. S. Related Collections Related Article Social Bookmarking                            What's this?