Protein Linked to Destruction of Mitochondria in Huntington's Disease

Researchers studying the molecular mechanisms involved in Huntington's disease (HD) have identified a protein that binds to mutant huntingtin protein in the mitochondria of neurons, which results in destruction of the mitochondria and death of the nerve cells.

Huntington’s disease is caused by a dominant gene that encodes the huntingtin protein. The 5' end of the HD 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 seven and 35 repeats, while the mutated form of the gene has anywhere from 36 to 180 repeats. The mutant form of huntingtin is broken down into toxic peptides, which contribute to the pathology of the syndrome.


Investigators at Case Western Reserve University (Cleveland, OH, USA) have been searching for factors that interact with mutant huntingtin protein to better understand the initial steps of Huntington’s disease progression. To this end they conducted proteomic analyses, which identified valosin-containing protein (VCP) as a mutant huntingtin-binding protein on the mitochondria.

VCP is an ATPase enzyme present in all eukaryotes. Its main function is to segregate protein molecules from large cellular structures such as protein assemblies, organelle membranes, and chromatin, and thus facilitate the degradation of released polypeptides by the multi-subunit protease proteasome.

The investigators reported in the August 26, 2016, online edition of the journal Nature Communications that VCP was selectively translocated to the mitochondria, where it was bound to mutant huntingtin protein in various HD models. VCP accumulated in mitochondria elicited excessive mitophagy (degradation of the mitochondria) and caused neuronal cell death.

Blocking huntingtin/VCP mitochondrial interaction with a peptide, HV-3, abolished VCP translocation to the mitochondria, corrected excessive mitophagy, and reduced cell death in HD mouse- and patient-derived cells and HD transgenic mouse brains. Treatment with HV-3 reduced behavioral and neuropathological phenotypes of HD in both fragment- and full-length huntingtin transgenic mice. These findings demonstrated a causal role of mutant huntingtin-induced VCP mitochondrial accumulation in HD pathogenesis and suggested that the peptide HV-3 might be a useful tool for developing new therapeutics to treat HD.

“Because mitochondrial dysfunction has been proposed to play an important role in the pathogenesis of Huntington’s disease, we investigated the binding proteins of mutant huntingtin on mitochondria,” said senior author Dr. Xin Qi, assistant professor of physiology and biophysics at Case Western Reserve University. “We found that VCP is a key player in mitochondria-associated autophagy, a mitochondria self-eating process. Over-accumulation of VCP on mitochondria thus results in a great loss of mitochondria, which leads to neuronal cell death due to lack of energy supply.”

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