Molecular Interactions Identified That Block Protein Transfer into Mitochondria of Huntington's Disease Neurons

The 5' end of the Huntington's disease gene has a sequence of three DNA bases, cytosine-adenine-guanine (CAG), coding for the amino acid glutamine, that is repeated multiple times. Normal persons have a CAG repeat count of between 7 and 35 repeats, while the mutated form of the gene has anywhere from 36 to 180 repeats. The mutant form of Htt is broken down into toxic peptides, which contribute to the pathology of the syndrome.

Investigators at the Washington University School of Medicine (St. Louis, MO, USA) and their colleagues at the University of Pittsburgh (PA, USA) worked with in vitro culture models and with a mouse model that mimicked the early stages of Huntington's disease.

They reported in the May 18, 2014, online edition of the journal Nature Neuroscience that recombinant mutant Htt directly inhibited mitochondrial protein import in their culture model. Furthermore, mitochondria from the brain synaptosomes of presymptomatic Huntington's disease model mice and from mutant Htt-expressing primary neurons exhibited a protein import defect, suggesting that deficient protein import was an early event in Huntington's disease.

At the molecular level, the investigators spotted interactions between mutant Htt and the TIM23 (translocase of inner mitochondrial membrane 23) mitochondrial protein import complex. Overexpression of TIM23 complex subunits attenuated the mutant Htt–induced mitochondrial import defect and subsequent neuronal death, which demonstrated that deficient mitochondrial protein import caused mutant Htt-induced neuronal death.

“We showed the problem could be fixed by making cells overproduce the proteins that make this transfer possible,” said first author Dr. Hiroko Yano, assistant professor of neurological surgery, neurology, and genetics at the Washington University School of Medicine. “We do not know if this will work in humans, but it is exciting to have a solid new lead on how this condition kills brain cells.”

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Washington University School of Medicine
University of Pittsburgh