Features | Partner Sites | Information | LinkXpress
Sign In
GLOBETECH PUBLISHING
GLOBETECH PUBLISHING
JIB

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

By BiotechDaily International staff writers
Posted on 08 Jul 2014
Image: A microscope image of a neuron with inclusion (stained orange) caused by Huntington\'s disease (Photo courtesy of Wikimedia Commons).
Image: A microscope image of a neuron with inclusion (stained orange) caused by Huntington\'s disease (Photo courtesy of Wikimedia Commons).
Researchers have identified a protein complex that interacts with the mutated form of huntingtin protein to impair transport of proteins into the mitochondria of brain cells, which leads to their malfunction and the loss of neurons that characterizes Huntington's disease.

Huntington’s disease is caused by a dominant gene that encodes a protein known as huntingtin (Htt). 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.”

Related Links:

Washington University School of Medicine
University of Pittsburgh 



comments powered by Disqus

Channels

Drug Discovery

view channel
Image: Synthetic ion transporters can induce apoptosis by facilitating chloride anion transport into cells (Photo courtesy of the University of Texas, Austin).

Experimental Drug Kills Cancer Cells by Interfering with Their Ion Transport Mechanism

An experimental anticancer drug induces cells to enter a molecular pathway leading to apoptosis by skewing their ion transport systems to greatly favor the influx of chloride anions. To promote development... Read more

Therapeutics

view channel
Image: Liver cells regenerated in mice treated with a new drug (right) compared with a control group (center) after partial liver removal. Healthy liver cells are shown at left (Photo courtesy of Marshall et al, 2014, the Journal of Experimental Medicine).

New Drug Triggers Liver Regeneration After Surgery

Investigators have revealed that an innovative complement inhibitor decreases complement-mediated liver cell death, and actually stimulates postsurgery liver regrowth in mice. Liver cancer often results... Read more

Lab Technologies

view channel

White-Matter Deficits Found in Codeine-Containing Cough Syrup Users

A magnetic resonance imaging (MRI) study of chronic users of codeine-containing cough syrups (CCS) has found deficits in specific regions of brain white matter and linked these changes with increased impulsivity in codeine-containing cough syrup users. These findings were consistent with findings from earlier research of... Read more

Business

view channel

Partnership Established to Decode Bowel Disease

23andMe (Mountain View, CA,USA), a personal genetics company, is collaborating with Pfizer, Inc. (New York, NY, USA), in which the companies will seek to enroll 10,000 people with inflammatory bowel disease (IBD) in a research project designed to explore the genetic factors associated with the onset, progression, severity,... Read more
 
Copyright © 2000-2014 Globetech Media. All rights reserved.