A GABA neuron made from human stem cells in the laboratory of University of Wisconsin-Madison neuroscientist Su-Chun Zhang. GABA neurons are the brain cells whose degradation causes Huntington’s disease, a condition characterized by severely degraded motor function, among other things. Zhang and his colleagues have shown that the severe motor deficits observed in a mouse model of Huntington’s can be corrected by implanting the laboratory-made cells. Image: Su-Chun Zhang |
Huntington’s
disease, the debilitating congenital neurological disorder that progressively
robs patients of muscle coordination and cognitive ability, is a condition
without effective treatment, a slow death sentence.
But if
researchers can build on new research reported in Cell Stem Cell, a special type of brain cell
forged from stem cells could help restore the muscle coordination deficits that
cause the uncontrollable spasms characteristic of the disease.
“This is
really something unexpected,” says Su-Chun Zhang, a University of Wisconsin-Madison neuroscientist and the senior author of
the new study, which showed that locomotion could be restored in mice with a Huntington’s-like
condition.
Zhang is an
expert at making different types of brain cells from human embryonic or induced
pluripotent stem cells. In the new study, his group focused on what are known
as GABA neurons, cells whose degradation is responsible for disruption of a key
neural circuit and loss of motor function in Huntington’s patients. GABA neurons, Zhang
explains, produce a key neurotransmitter, a chemical that helps underpin the
communication network in the brain that coordinates movement.
In the
laboratory, Zhang and his colleagues at the UW-Madison Waisman Center
have learned how to make large amounts of GABA neurons from human embryonic
stem cells, which they sought to test in a mouse model of Huntington’s disease.
The goal of the study, Zhang notes, was simply to see if the cells would safely
integrate into the mouse brain. To their astonishment, the cells not only
integrated but also project to the right target and effectively reestablished
the broken communication network, restoring motor function.
The results of
the study were surprising, Zhang explains, because GABA neurons reside in one
part of the brain, the basal ganglia, which plays a key role in voluntary motor
coordination. But the GABA neurons exert their influence at a distance on cells
in the midbrain through the circuit fueled by the GABA neuron chemical
neurotransmitter.
“This
circuitry is essential for motor coordination,” Zhang says, “and it
is what is broken in Huntington
patients. The GABA neurons exert their influence at a distance through this
circuit. Their cell targets are far away.”
That the
transplanted cells could effectively reestablish the circuit was completely
unexpected: “Many in the field feel that successful cell transplants would
be impossible because it would require rebuilding the circuitry. But what we’ve
shown is that the GABA neurons can remake the circuitry and produce the right
neurotransmitter.”
The implications
of the new study are important not only because they suggest it may one day be
possible to use cell therapy to treat Huntington’s,
but also because it suggests the adult brain may be more malleable than
previously believed.
The adult brain,
notes Zhang, is considered by neuroscientists to be stable, and not easily
susceptible to therapies that seek to correct things like the broken circuits
at the root of conditions like Huntington’s.
For a therapy to work, it has to be engineered so that only cells of interest
are affected. “The brain is wired in such a precise way that if a neuron
projects the wrong way, it could be chaotic.”
Zhang stresses
that while the new research is promising, working up from the mouse model to
human patients will take much time and effort. But for a disease that now has
no effective treatment, the work could become the next best hope for those with
Huntington’s.
Filed Under: Drug Discovery
