Track what motor proteins deliver to healthy cells and explore what's happening in neurological disorders

Scientists say motor proteins that run natural channels on our cytoskeleton are carrying goods necessary for life and can also lead to disease
.

They are working to understand what this highly regulated transport system normally transmits, so they can also discover what can and cannot be transmitted in inherited neurological disorders that deprive them of the ability to
walk and breathe.

Dr.
Graydon B.
Gonzalwitz, a cell biologist in the Department of Cell Biology and Anatomy at the Georgia School of Medicine at Augusta University, said: "We're trying to understand how these motors get
things where they need to go.
" "We're trying to figure out how it works and what substance it attaches to, because mutations in substances related to dynein, both the carrier of dynein and the dynein itself, are associated with
a range of neurological diseases.
"

The dynein cited by Gonsalves is a family
of motor proteins associated with diseases such as spinal muscular atrophy.
Spinal muscular atrophy is a group of genetic disorders in which motor neurons in the spinal cord are killed, affecting basic functions such as walking and breathing, as well as the progressive genetic neurological disease Chart-Marie-tooth
.

Gonsalvez is the principal investigator of a new grant of $1.
9 million (R35GM145340) from the National Institute of General Medical Sciences, which allows him to focus on this basic biological function and ultimately better understand how these diseases occur and how to intervene
.

Molecular motors that Gonsalves calls "carts" transport proteins — the body's basic building blocks and drivers of biological activity — and the RNA that can make extra proteins to the right place
.

The motor moves on the path of the cytoskeleton or cytoskeleton and functions very similarly to our large skeleton, shaping the cell
.
It's an ongoing process, he says, because the proteins delivered by the motor wear out or need to move
for some reason.
He noted that life inside cells can be a destructive place
.
But motor proteins are busiest during development, like building a new home rather than updating
an existing one.
If the movements are not correct, the developing baby will not survive
.
All of these activities establish and maintain cellular polarity
.

Going back to the analogy of a residential building, basically cellular polarity refers to the fact that the content is located inside the cell, just like the room and objects are located in the home, which makes it functional
.
But in cells, the problem of location is much more serious because the loss of polarity is incompatible with life, he said
.

"There are different regions in the cell that do specific things, and proteins, RNA, and vesicles need to be sequenced," he says of strategic movement and placement
.

While these differences are subtle, Gonsalvez says, for example, when a normal cell becomes cancerous, its polarity changes
because of changes in function.
Conversely, in good health, polarity does not change
much even with age.

In the case of these neurological disorders, he said, these changes are genetic mutations that may even be repaired
by gene-editing technologies such as CRISPR.

"All of these diseases are dysfunctional diseases, missing something
subtle, with significant implications," he said.

Motor proteins don't work alone, they have cargo adapters, sort of like motorized trailers, that connect together to allow them to carry more cargo
.
Gonsalvez said mutations in cargo adapters are known to cause disease as well, but not much is known in
detail.
But he believes that a major problem is that these cargo adapters cannot attract and/or grab the right cargo because of the mutation
.

He noted that motor proteins are unidirectional, each with a specific direction, in which case dynein transports the cargo along a long road to the center of the cell, where it releases the cargo, separates, dismantles, and then repeats it all
.
Kines are another group of motor proteins that take substances away from cells but have also been linked to diseases, including amyotrophic lateral sclerosis
.

Figuring out what engine proteins and their cargo adapters carry is not an easy task
.
First of all, these motors must release their cargo when they reach their destination, so by design, their connection to the cargo is relatively weak, which means that standard biochemical methods do not work to analyze what they load, because they will only make the load fall apart
.

Instead, Gonsalvez and his team used a biotin ligase technique that connects small clumps of vitamin B to the motor and anything near it, such as the proteins
it carries.
They then added another natural protein, streptavidin, which naturally binds to biotin, allowing them to purify engines and cargo
.
Next, they used precise analytical methods, such as mass spectrometry and proteomics, to find out exactly what engine proteins bind
to.
They first used this method to look at the fruit fly egg because it is readily available, but is now transitioning to the fly's head, which is actually full of neurons and motor proteins that function the same as those of humans, including having the same amino acids
that may mutate in dynein.

"There are disease-related mutations in these engines and their cargo adapters, but why are they disease-related?" Gonsalvez said
.
"People think they have deficiencies
in transportation.
Maybe the diseases are because they haven't moved X, Y, Z where they need to be, but we don't know what X, Y, Z is
.
We don't know what's missing," he said
.

Gonsalvez says that while you can't give humans new power, at least not yet, if you can understand what X, Y, and Z are, it's possible to deliver more protein X to the center of the cell that
needs it in other ways.

When the "missing factor" is identified, testing will be needed to ensure that when a particular protein is MIA or its mutated version is delivered, it actually causes disease
.
"But first you have to identify the goods, and that's what we do," Gonzalez said
of connecting those important points.

Once they know what is normal, they can compare it to what can lead to potentially devastating neurological disorders and find a difference
.

"Everything in our body is in constant motion, and it's through motors
," says Gonsalvez.
He noted that even the path of motor protein movement is moving
.
When cells that are able to divide divide, such as skin cells that divide rapidly to replace our cells that we keep shedding, these channels are also torn apart and reassembled
.

He points out that motor proteins don't move unless there's something to carry, because it's a waste of precious energy, and instead, the motors only start working when the cargo adapters are bound to them
.
So far, among the diseases studied, cargo adapters are present
.