Disruption of gene used to transport proteins leads to ALS

December 11, 2012 by Brian Wallheimer, Purdue University
James Clemens found that a gene - that when mutated leads to a genetic version of amyotrophic lateral sclerosis - is critical for cell signaling in neurons. Credit: Purdue Agricultural Communication photo/Tom Campbell

(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.

James Clemens, an assistant professor of biochemistry, found that a gene called VAPB is responsible for transporting certain proteins to their proper places along . When the gene is mutated or deleted, these proteins are unable to make it to locations in neurons where their function is critically required.

ALS causes neurons to die, slowly eliminating voluntary muscle control and eventually causing death in about five out of 100,000 people worldwide, according to the National Institutes of Health. About 90 percent of the cases are considered sporadic, with no known risk factor. The other 10 percent is due to an inherited genetic defect.

Clemens studied the VAPB gene, which, when mutated, causes a portion of the disease's genetic versions. Using Drosophila, or the fruit fly, as a model, his laboratory determined that VAPB is critical to delivering a cell surface receptor called Dscam - Down syndrome cell adhesion molecule - to the neuron's axons.

"VAPB is important for the trafficking of Dscam and potentially other cell surface receptors down axons," said Clemens, whose findings were published in The Journal of Neuroscience. "This may be the reason why people with mutations of VAPB develop ALS."

Dscam is important for proper neural function. When communication between neurons is disrupted, they undergo programmed cell death. If a neuron dies, it disrupts the signaling chain from the brain to muscles, which results in neurodegenerative diseases, Clemens said.

"Neurons are all connected. The axon of one neuron sends signals to the dendrites of the next neuron in the circuit." Clemens said. "If Dscam and other receptors are not delivered to their proper locations in axons, then the connections between axons and dendrites are destabilized, resulting in neuron degeneration."

In experiments using the Drosophila version of VAPB, the loss of the gene eliminated the amount of Dscam found around the axons of neural cells.

"These findings expand our understanding of the normal cellular functions of VAPB and uncover new molecular mechanisms that potentially underlie the development of ALS," Clemens said. "We hope that our discovery in fruit flies will ultimately lead to the development of new clinical strategies to detect, treat or prevent ALS."

Clemens said it would be important to understand the functions of proteins that VAPB directs to a neuron's axons. His work was funded by the Klingenstein Foundation, the ALS Association and the Canadian Institutes of Health Research.

Explore further: Stem cell model offers clues to cause of inherited ALS

More information: Drosophila VAP-33 is Required for Axonal Localization of Dscam Isoforms, Zhen Yang, Sung Un Huh, J. Michelle Drennan, Hitesh Kathuria, Juan S. Martinez, Hiroshi Tsuda, Mark C. Hall, and James C. Clemens, The Journal of Neuroscience, 2012.

ABSTRACT
Mutations in VAPB have been identified in a familial form of amyotrophic lateral sclerosis (ALS), and reduced VAPB levels have been found in patients with sporadic ALS. Vap protein family members from different species and cell types have been implicated in a number of cellular functions, but how Vap dysfunction in neurons and/or muscles contributes to motor neuron degeneration and death is poorly understood. Using Drosophila as a model organism, we show that Vap physically interacts with and affects the axonal functions of the Down syndrome cell adhesion molecule (Dscam). Dscam is a cell-surface receptor involved in axon and dendritic patterning and neuron self-recognition and avoidance. Alternative splicing of the Dscam transcript leads to the production of Dscam isoforms that contain one of two possible transmembrane (TM) domain and flanking sequences that either restrict the isoform to dendrites and cell bodies (TM1) or target the isoform to axon processes (TM2). We find that Vap specifically interacts with Dscam isoforms that contain the TM2 cytoplasmic juxtamembrane flanking sequences. Using loss-of-function genetics, we further show that Vap is required for localization of Dscam isoforms containing TM2 to axons and that Vap loss suppresses Dscam gain-of-function axon phenotypes. We propose that Vap function is required in neurons to selectively traffic proteins to axons, and disruption of this function may contribute to the pathology of ALS.

Related Stories

Stem cell model offers clues to cause of inherited ALS

June 21, 2011
An international team of scientists led by researchers at the University of California, San Diego School of Medicine have used induced pluripotent stem cells (iPSCs) derived from patients with amyotrophic lateral sclerosis ...

New gene mutations linked to amyotrophic lateral sclerosis and nerve cell growth dysfunction

July 15, 2012
Researchers have linked newly discovered gene mutations to some cases of the progressive fatal neurological disease amyotrophic lateral sclerosis – ALS, also known as Lou Gehrig's disease. Shedding light on how ALS destroys ...

Disease progression halted in rat model of Lou Gehrig's disease

December 12, 2011
Amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease) is an incurable adult neurodegenerative disorder that progresses to paralysis and death. Genetic mutations are the cause of disease in 5% of patients ...

Oligodendroglia cells protect neurons against neurodegeneration

July 11, 2012
(Medical Xpress) -- Johns Hopkins researchers say they have discovered that the central nervous system's oligodendroglia cells, long believed to simply insulate nerves as they "fire" signals, are unexpectedly also vital to ...

New discovery may block ALS disease process

April 19, 2011
New Orleans, LA –In the first animal model of Amyotrophic Lateral Sclerosis (ALS), developed by Dr. Udai Pandey, Assistant Professor of Genetics at LSU Health Sciences Center New Orleans, Dr. Pandey's lab has found in ...

Scientists identify mutation in SIGMAR1 gene linked to juvenile ALS

August 12, 2011
Researchers from the Kingdom of Saudi Arabia have identified a mutation on the SIGMAR1 gene associated with the development of juvenile amyotrophic lateral sclerosis (ALS). Study findings published today in Annals of Neurology, ...

Recommended for you

Research reveals atomic-level changes in ALS-linked protein

January 18, 2018
For the first time, researchers have described atom-by-atom changes in a family of proteins linked to amyotrophic lateral sclerosis (ALS), a group of brain disorders known as frontotemporal dementia and degenerative diseases ...

Fragile X finding shows normal neurons that interact poorly

January 18, 2018
Neurons in mice afflicted with the genetic defect that causes Fragile X syndrome (FXS) appear similar to those in healthy mice, but these neurons fail to interact normally, resulting in the long-known cognitive impairments, ...

How your brain remembers what you had for dinner last night

January 17, 2018
Confirming earlier computational models, researchers at University of California San Diego and UC San Diego School of Medicine, with colleagues in Arizona and Louisiana, report that episodic memories are encoded in the hippocampus ...

Recording a thought's fleeting trip through the brain

January 17, 2018
University of California, Berkeley neuroscientists have tracked the progress of a thought through the brain, showing clearly how the prefrontal cortex at the front of the brain coordinates activity to help us act in response ...

Midbrain 'start neurons' control whether we walk or run

January 17, 2018
Locomotion comprises the most fundamental movements we perform. It is a complex sequence from initiating the first step, to stopping when we reach our goal. At the same time, locomotion is executed at different speeds to ...

Miles Davis is not Mozart: The brains of jazz and classical pianists work differently

January 16, 2018
Keith Jarret, world-famous jazz pianist, once answered in an interview when asked if he would ever be interested in doing a concert where he would play both jazz and classical music: "No, that's hilarious. [...] It's like ...

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.