Inside a single fruit fly larva neuron, Huntingtin proteins
(red) and Rab7 proteins (green) travel along microtubule structures
that act as highways, transporting materials from one part of the
cell to another. The yellow dots show where Huntingtin and Rab7 are
traveling together (red and green fluorescent tags appear yellow
when combined). Credit: Shermali Gunawardena
BUFFALO, N.Y. — We've known for years that the Huntingtin
protein (Htt) is responsible for Huntington's disease, a
neurodegenerative disorder that diminishes a person's mental and
Create the protein in the wrong form in the human body, and
symptoms develop. But why this happens — why mutations
in the protein cause disease — is a question that has yet to
A new study by University at Buffalo researchers marks a step
toward understanding this enigma. The research, published
Oct. 8 in the journal Human Molecular Genetics, shows that Htt
controls the movement of precious cargo traveling up and down
neurons, the cells that form the core of the nervous system in
You can literally see this regulation in action: Videos and
microscope photos taken by the research team show Htt moving along
neuronal highways in concert with precious materials called Rab
proteins, which are vital for normal cellular function.
When scientists lowered the amount of non-mutant Htt available,
the movement of four different Rab proteins was altered, with the
proteins either slowing down or speeding up. Slowing down resulted
in traffic jams that blocked other important cargo from traveling
in a timely manner to desired destinations in neurons.
The research was done in fruit fly larvae, but all four Rab
proteins studied are present in human neurons, and the cellular
mechanisms at play are expected to be found in people too.
“The problem with the Huntingtin protein is that we know
it’s linked to Huntington’s disease, but we don’t
have a full understanding of what the protein’s normal
function is — what purpose it serves in the body, and why
problems with it lead to disease,” says lead researcher
Shermali Gunawardena, PhD, associate professor of biological
sciences in UB’s College of Arts and Sciences.
“Our research begins to unravel the mystery of how Htt is
involved in Huntington’s disease,” she says. “If
we can better understand the role that Htt plays in the body,
inside cells, we can perhaps create therapeutics that address the
disease at an early stage, before symptoms become
Gunawardena says it’s possible that the neuronal traffic
jams her team observed could contribute to the formation of
inclusions — dangerous aggregations of proteins that have
been found in the neurons of patients with Huntington’s
Inside neurons, a network of microtubule structures serves as a
highway system, enabling the transport of materials from one part
of a cell to another. The vehicles that ferry cargo along these
roadways are vesicles — tiny, membranic structures that
enclose or otherwise carry materials ranging from neurotransmitters
to chemicals used in cellular repair.
The proper functioning of this highway system is necessary for
the proper functioning of cells, and the new UB study illuminates
the role that Htt plays in keeping the roadways humming.
The research focused on Htt’s influence on Rab proteins,
which travel with vesicles along neuronal highways and are thought
to be necessary for vesicle formation and movement.
There are 75 known Rab proteins, and the study looked at the 16
Rabs that are found in both fruit fly and human neurons. When
researchers reduced levels of normal Htt in the neurons of fruit
fly larvae, it:
- Slowed the movement of two Rab proteins — Rab3 and Rab19
— along with the vesicles attached to the proteins. Movement
was slowed for proteins moving both toward and away from the
neurons’ main cell body.
- Slowed the movement of Rab7 protein and associated vesicles,
but only for those moving toward the central cell body.
- Sped up the movement of Rab2 protein and associated vesicles,
but only for those moving away from the central cell body.
Each of these Rab vesicle complexes may transport different
materials within neurons and have functions that are vital to the
health of the nervous system, so changes in their movement could
lead to neurological problems, Gunawardena says.
"Our research starts to create a picture of how Htt may
contribute to disease,” Gunawardena says. “If HTT is
needed for particular aspects of movement of Rabs and in turn the
function of certain Rabs, then ensuring that this pathway is not
disrupted could provide a new therapeutic avenue for a disease that
is not treatable.”
In addition to Rabs 3, 19, 7 and 2, the movement of a fifth Rab
protein was also affected, but researchers are still analyzing
findings related to this fifth protein, Gunawardena says. The other
Rab proteins studied were not impacted by the reduction of Htt.
The study was funded by the National Institute of Neurological
Disorders and Stroke and in part by the John R. Oishei