Balancing Mitochondrial Division Critical in Treating Huntington's Disease

The mutated gene adds from one to many dozens of extra glutamine molecules to Htt. Incomplete breakdown of the enlarged protein results in the buildup of toxic, misfolded peptides that destroy cells in the nervous system. The mechanisms of mutant huntingtin-mediated neurotoxicity have been unclear; however, mitochondrial dysfunction is a key event in Huntington's disease pathogenesis.

Investigators at the University of Central Florida (Orlando, USA) showed in a study published in the February 20, 2011, online edition of the journal Nature Medicine that mutant huntingtin triggered mitochondrial fragmentation in rat neurons and in fibroblasts of individuals with Huntington's disease in vitro, and in a mouse model of Huntington's disease in vivo, before the appearance of neurological defects and huntingtin aggregates.

Mutant huntingtin abnormally interacted with the mitochondrial fission GTPase dynamin-related protein-1 (DRP1) in mice and humans with Huntington's disease, which, in turn, stimulated its enzymatic activity. Dynamin-1 is a member of the dynamin subfamily of GTP-binding proteins. This protein possesses unique mechanochemical properties used to tubulate and sever membranes, and is involved in clathrin-mediated endocytosis and other vesicular trafficking processes.

Mutant huntingtin–mediated mitochondrial fragmentation, mitochondrial transport, and neuronal cell death were all reversed by reducing DRP1 GTPase activity.

"Mitochondria require balanced cycles of division and fusion to maintain their ability to produce energy," said senior author Dr. Ella Bossy-Wetzel, professor of biomedical sciences at the University of Central Florida. "The protein DRP1 is needed for mitochondrial division. We found that in Huntington's disease, DRP1 becomes overactive and causes too much mitochondrial division without balancing fusion.”

"The next step will be to test the DRP1 function in animals and patients to see whether the protein also protects the brain,” said Dr. Bossy-Wetzel. "This could be done before the onset of disease in patients who have the mutant Huntington gene, but have no neurological symptoms. The hope is that we might be able to delay the onset of disease by improving the energy metabolism of the brain.”

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