Blocking nuclear export seemed to prevent cells from dying and counteracted the defects in neurons
with mutant Huntingtin, the researchers say.
The researchers showed that mice
with mutant huntingtin had mitochondria full of VCP, as did nerve cells donated by people with Huntington's disease.
The researchers worked to identify ways to prevent VCP from heading to nerve cell mitochondria and interacting
with mutant huntingtin protein once inside.
Xin Qi, PhD, assistant professor of physiology and biophysics at Case Western Reserve University School of Medicine has been looking for proteins that interact
with mutant huntingtin to better understand the initial steps of Huntington's disease progression.
Not exact matches
This abnormal binding causes more VCP accumulation on the mitochondria,» Nerve cells
with VCP -
mutant huntingtin interacting inside them became dysfunctional and self - destructed.
University of California, Irvine neurobiologists Leslie Thompson and Joseph Ochaba
with the Departments of Neurobiology & Behavior and Psychiatry & Human Behavior and their colleagues from UCI and from Children's Hospital of Philadelphia have shown that reducing the aberrant accumulation of a particular form of the
mutant Huntingtin protein corresponds to improvement in symptoms and neuroinflammation in HD mice.
They cleverly designed a small protein, or peptide,
with the same regions to disrupt the VCP -
mutant huntingtin protein interaction.
The VCP inside mitochondria only interacted
with mutant, but not healthy
huntingtin protein.
The test, called a «single molecule counting assay», combines fluorescent antibodies
with a laser detection chamber to count individual molecules of
mutant huntingtin with a very low detection threshold.
Next, Grima looked at cell death in cultured neurons
with a healthy or a
mutant form of
Huntingtin, or
with a
mutant form of
Huntingtin that was treated
with small amounts of an experimental drug called KPT - 350, one that prevents a nuclear export protein, Exportin - 1, from shuttling proteins and RNA out of the nucleus.
Grima used two mouse models of Huntington's disease: one
with a human version of the
mutant Huntingtin protein and another
with an aggressive form of the disease that contains only the first portion of the mouse
Huntingtin protein.
Neurons
with the healthy version of
Huntingtin had about 18 percent die off, and neurons
with the
mutant version of
Huntingtin had about 38 percent die off.
R6 / 2 mice have been genetically altered
with an abnormal gene that makes them produce a harmful fragment of the
mutant huntingtin protein
Any effects were small compared
with the desirable action on the
mutant huntingtin gene.
«Huntington's — an inherited and fatal disorder that leads to problems
with muscle coordination, cognition and personality — is characterized by the toxic buildup of a
mutant form of the
huntingtin protein in the brain,» explained Dr. Finkbeiner, who directs the Taube - Koret Center for Neurodegenerative Disease Research at Gladstone.
Using neurons extracted from rodent models of Huntington's, the team employed the OPL method, which tracked the speed and efficiency
with which different types of neurons were able to break down and dissolve the
mutant huntingtin.
Emphasising their desire to move the drug forward, in a separate announcement made directly to the HD community, Ionis said «Upon study completion, the next step for this program will be to conduct a study to investigate if decreasing
mutant huntingtin protein
with IONIS - HTTRx can slow the progression of this terrible disease.»
We've known for a little while that drugs that interfere
with mTOR decrease levels of
mutant huntingtin protein by helping cells destroy it after it's made.
Mutant huntingtin, although altered, is still present, and most people
with HD have normal
huntingtin, too.
For example, if we block
mutant huntingtin production in cells or animals
with «gene silencing» techniques, how can we confirm that this treatment actually does what it's supposed to do in the brains of patients
with HD?