Disruption of gene used to transport proteins leads to ALS

December 10, 2012 − by wpengine − in Archived − Comments Off on Disruption of gene used to transport proteins leads to ALS

December 10, 2012

John Clemens als

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.
(Purdue Agricultural Communication photo/Tom Campbell)

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WEST LAFAYETTE, Ind. – 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 neurons. 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.

Writer: Brian Wallheimer,
765-496-2050, [email protected]

Source: James Clemens,
765-494-1087, [email protected]


ABSTRACT

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

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.


Ag Communications: (765) 494-2722;
Keith Robinson, [email protected]
Agriculture News Page





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