Jammed molecular motors may play a role in the development of ALS

June 12, 2013, University of Illinois at Chicago

Slowdowns in the transport and delivery of nutrients, proteins and signaling molecules within nerve cells may contribute to the development of the neurodegenerative disorder ALS, according to researchers at the University of Illinois at Chicago College of Medicine.

The researchers showed how a genetic mutation often associated with inherited ALS caused delays in the transport of these important molecules along the long axons of neurons.

Their findings were published in the online journal PLOS ONE on June 12.

Motor neurons are among the longest cells in the human body—some may extend half a person's height, as much as three feet. This poses a problem if all the cellular building blocks are made at one end of the cell, where the nucleus sits, but are needed at the other end of the cell.

Neurons have the molecular equivalents of highways and and motor proteins—that run along their long axons, ferrying material back and forth. But when shipping is held up, and products aren't getting to where they are needed, the cell can't function optimally. These transport problems can cause neurons to lose contact with other neurons and muscles.

"If the transport process is delayed or slowed, the terminal end of the cell can run out of materials it needs, and can lose its synaptic connection with its neighboring neurons," says Gerardo Morfini, UIC assistant professor of anatomy and cell biology and the co-principal investigator on the study. "Without the connections, the cells die."

"Cell death is the final stage in a long disease process in ALS," said Scott Brady, UIC professor and head of anatomy and and co-principal investigator. "We wanted to understand the in neurons leading up to cell death."

Neuroscientists know that mutations in a protein called SOD1 account for many of the 10 percent of ALS cases that are inherited. Ninety percent of ALS cases have no known cause and are termed sporadic.

Brady and colleagues had previously shown, using high-resolution video microscopy of squid axons, that a mutant variant of the protein significantly slowed down the transport of material from one end of the cell to the other.

In the new study, the researchers looked at how the mutated form of SOD1 caused the slowdown in cellular transport. They found that the mutated protein activated molecules called p38 kinases, which in turn modified a major motor protein involved in moving cargo along the nerve axons. These modified moved poorly compared to controls that were exposed to unmutated SOD1.

They also showed that transport in in genetically altered mice was also slowed by mutant SOD1, through the same mechanism.

"The pathways between SOD1 and the p38 kinases could provide interesting targets for therapeutic intervention in treating ALS, both for some of the genetic forms and the spontaneous forms, where malfunctioning SOD1 is also a contributing factor," said Brady.

Explore further: Increased stability of a misfolded protein linked to age of onset of common form of motor neuron disease

Related Stories

Increased stability of a misfolded protein linked to age of onset of common form of motor neuron disease

April 22, 2013
Neurodegenerative diseases are characterized by the aggregation of misfolded proteins, which accumulate to form insoluble clumps within or around nerve cells. In the adult motor neuron disease amyotrophic lateral sclerosis ...

Structure that edits messenger RNA transcripts defective in two different forms of motor neuron diseases

April 26, 2013
Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are degenerative motor neuron diseases in which the key mutated genes are involved in RNA metabolism. This similarity suggests that a common dysregulation ...

Disruption of gene used to transport proteins leads to ALS

December 11, 2012
(Medical Xpress)—A Purdue University biochemist has determined the function of a gene that when mutated leads to a genetic variation of amyotrophic lateral sclerosis, or Lou Gehrig's disease.

Amyotrophic lateral sclerosis trial shows novel therapy is safe

April 23, 2013
An investigational treatment for an inherited form of Lou Gehrig's disease has passed an early phase clinical trial for safety, researchers at Washington University School of Medicine in St. Louis and Massachusetts General ...

Recommended for you

Weight flux alters molecular profile, study finds

January 17, 2018
The human body undergoes dramatic changes during even short periods of weight gain and loss, according to a study led by researchers at the Stanford University School of Medicine.

Secrets of longevity protein revealed in new study

January 17, 2018
Named after the Greek goddess who spun the thread of life, Klotho proteins play an important role in the regulation of longevity and metabolism. In a recent Yale-led study, researchers revealed the three-dimensional structure ...

The HLF gene protects blood stem cells by maintaining them in a resting state

January 17, 2018
The HLF gene is necessary for maintaining blood stem cells in a resting state, which is crucial for ensuring normal blood production. This has been shown by a new research study from Lund University in Sweden published in ...

Magnetically applied MicroRNAs could one day help relieve constipation

January 17, 2018
Constipation is an underestimated and debilitating medical issue related to the opioid epidemic. As a growing concern, researchers look to new tools to help patients with this side effect of opioid use and aging.

Researchers devise decoy molecule to block pain where it starts

January 16, 2018
For anyone who has accidentally injured themselves, Dr. Zachary Campbell not only sympathizes, he's developing new ways to blunt pain.

Scientists unleash power of genetic data to identify disease risk

January 16, 2018
Massive banks of genetic information are being harnessed to shed new light on modifiable health risks that underlie common diseases.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.