Cell Rep: The role of brain proteins in movement disorders in children

Scientists at the University of North Carolina School of Medicine and the University of North Carolina Escherman School of Pharmacy, they collaborated with the team at Queen Mary University of London to elucidate the molecular events
of a genetic motor and neurodegenerative disease known as ARSACS.
ARSACS is an autosomal recessive spastic ataxia of Charlevoix-Saguenay, named
after the two Quebec valleys where the first case was found.

Children with ARSACS usually show difficulty walking at the age of two, after which they develop a series of neurological problems
.
The cerebellum is the area of the brain that coordinates movement and balance, and in individuals with ARSACS, a type of neuron called Purkinje cell dies
.
Most patients have to use a wheelchair between the ages of 30 and 40, and the average life expectancy is shortened
by the age of 55.

The disease is caused by genetic mutations and loss of function in the capsule, which encodes a very large protein called capsule protein, which has been difficult to study
directly due to its large size.
Relatively little
is known about its normal function and how its absence causes disease.
In the United States, the collaborating researchers conducted the most comprehensive analysis
of what happens inside cells when cyst proteins are missing.

"We're trying to take an unbiased approach to understanding what goes wrong
when cells lose their cyst proteins.
" Our findings suggest that the death of Purkinje cells in ARSACS may be due to changes in neuronal connections and synaptic structure," said study co-senior author Justin Wolter, PhD, a postdoctoral researcher
at the University of North Carolina Center for Neuroscience.

Another senior co-author of the study is Dr
Paul Chapple, professor of molecular cell biology at Queen Mary University of London.

The study began when teams at Chappell's lab and the University of North Carolina at Chapel Hill worked
without each other's knowledge.
"This project was initiated by Tammy Havener of the University of North Carolina's Escherman School of Pharmacy, and then joined by three postdoctoral researchers from different departments at the University of North Carolina — Wen Aw, Katherine Hixson, and myself," Wolter said
.
"When we realized that Lisa Romano of Chappell's lab had made similar discoveries in a different way, we all decided to join forces and move forward
together.
I think this is a great example of how open science and collaboration can pay off
for the community.
”

In this study, the researchers used several omics-based techniques in cultured human cells to detect how the loss of cyst protein alters protein levels and cell organization
.
They confirmed the presence of defects that had been noted in previous studies, such as abnormal aggregation of fibrous-forming structural proteins, defects in mitochondrial count, and dynamics, both of which are often observed
in many neurodegenerative diseases.

But they also found many anomalies
that had not been discovered before.
These include an excess of a protein called tau protein, a trajectory
of intracellular transport regulated by tau, and changes in microtubule dynamics.
The researchers found that the consequence of this change in transport is that many proteins cannot reach their proper locations
within the cell.
Of particular concern are the "synaptic adhesion" protein, which helps neurons form and maintain synapses—the connections
between neurons that send signals.
Consistent with these observations, the team found changes
in synaptic structure in a mouse model of ARSACS.
Importantly, these changes occur before
neurodegeneration occurs.

These findings expand the picture of how cyst proteins regulate a variety of cellular processes
.
They also raised the possibility that Purkinje cells — the
most affected neurons in ARSACS — may have died due to a lack of connectivity to other neurons.
The researchers will continue to conduct more in-depth research into these changes in the brain to understand whether this neurodegenerative disease originates from the process
of brain development.

The researchers note that while ARSACS may only affect a few thousand people worldwide, such research could have broader implications
.

"There seems to be a lot of overlap between ARSACS and other brain diseases," Chapple said
.
"For example, we show that in cells lacking cystin, tau protein biology is disrupted, and of course, tau protein abnormalities are also a well-known feature of
Alzheimer's disease.
" So we thought that studying this rare neurological disease could provide insights
into more common diseases.
”

"There's a lot of work to be done
to understand the mechanisms by which synaptic connectivity is affected, and whether it causes neuronal death," Wolter said.
"However, if that's the case, it could inform future treatments
.
"