Nav: Home

Syracuse U. researchers close to understanding 'disease mechanisms' of ALS

March 08, 2018

SYRACUSE, N.Y. - Syracuse University researchers are making strides in understanding the disease mechanism of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.

Carlos A. Castaneda, assistant professor of biology, chemistry and interdisciplinary neuroscience, and Thuy Dao, a postdoctoral researcher in chemistry, have been working with ubiquitin, a tiny molecule that tags obsolete proteins in a cell. They recently found that ubiquitin eliminates droplets of Ubiquilin-2 (UBQLN2) in solution.

The discovery is noteworthy, Castaneda says, because UBQLN2 is a protein-encoding gene, mutations to which cause ALS and various types of dementia, such as frontotemporal dementia (FTD).

"UBQLN2 is found in motor neuron inclusions of patients with ALS," he says. "We show that UBQLN2 undergoes liquid-liquid phase separation, in which proteins coalesce into protein-rich droplets to form membraneless organelles in cells. Interestingly, dysfunction of membraneless organelle assembly and disassembly is emerging as a common pathogenic mechanism of ALS and other neurodegenerative disorders."

The ALS Association supports the duo's research, which in turn is the subject of a major paper in the journal Molecular Cell (Elsevier, 2018).

Other authors include Brian Martyniak G'18, a second-year Ph.D. student in chemistry and biochemistry, who belongs to Castaneda's lab; members of J. Paul Taylor's research group from both St. Jude Children's Research Hospital and the Howard Hughes Medical Institute; and members of Heidi Hehnly's lab at SUNY Upstate Medical University.

"We want to understand the mechanisms that trigger motor neurons to degenerate in ALS," says Castaneda, the paper's lead contact. "It appears that pathological stress granules--membraneless organelles thought to be formed by liquid-liquid phase separation of RNA-binding proteins--trigger ALS and related disorders, leading to cell death."

Scientists know that when a eukaryotic cell is under stress, it causes certain proteins and RNA to form stress granules (SGs). While this is normal behavior, persistence of SGs or dysregulation of SG dynamics can promote disease states.

Castaneda and Dao, in collaboration with Taylor's group, showed that UBQLN2 was "recruited" to SGs. "This gives our work potential ALS relevance, since mutations in UBQLN2 might lead to defects in either SG assembly, or SG disassembly, or both," Castaneda says.

There are billions of neurons, or nerve cells, in the nervous system. (The brain alone has more than 100 billion of them.) When ALS attacks neurons, their corresponding muscles weaken and die. People with ALS eventually lose the ability to speak, eat, move or breathe.

Castaneda, who studies proteins associated with neurodegenerative and neuromuscular disease, explains that muscle weakness or stiffness is usually the first sign of ALS: "It is followed by atrophy and paralysis of the muscles of the limbs and trunk, and of the muscles controlling vital functions. The average survival time is three years after diagnosis."

Ubiquitin and UBQLN2 are part of what of Castaneda calls a "quality-control mechanism," which maintains proteins at their proper levels during the lifespan of a cell. (Unlike other cells, which live several days or weeks, neurons typically last an entire lifetime.) Any kind of disruption to protein homeostasis usually impairs neuronal development and function.

"We postulated--and eventually confirmed with microscopy and nuclear magnetic resonance spectroscopy--that ubiquitin disrupts UBQLN2 liquid-liquid phase separation," says Castaneda, who joined Syracuse's faculty in 2014. "This was significant because ubiquitin tags many proteins, at one point or another."

Castaneda ultimately hopes to redirect UBQLN2 out the "ubiquinated" substrates in SGs and into protein quality-control pathways. "UBQLN2 is like a shuttle, ferrying misfolded proteins to the cell's protein-recycling plant," he continues. "Under normal conditions, SGs dissipate when the stress condition is removed. However, if the condition impairs SG assembly in any way, ALS-linked RNA-binding proteins begin to aggregate."

While there is no cure for ALS, many people with the disease live longer, thanks to clinical management and two FDA-approved drugs: riluzole and radicava.

Castaneda is optimistic his innovative work with ubiquitin and UBQLN2 will achieve a greater understanding of ALS' molecular mechanisms and lead to a cure. "UBQLN2 interacts with other RNA-binding proteins, including TDP-43, which is found in 97 percent of inclusions of patients diagnosed with familial or sporadic ALS," he says. "I look forward to investigating these interactions."

Studies show that most people who develop ALS are between the ages of 40 and 70, with the disease being 20 percent more common in men. Although scientists struggle to determine the specific genetics or environmental factors that trigger ALS, they find that military veterans, particularly those deployed in the Gulf War from 1990-91, are twice as likely to develop the disease.

"Defects in protein recycling contribute to neurodegeneration," Castaneda says. "The more we understand UBQLN2's biological functions--specifically, how its mutations lead to ALS--the better able we can develop new therapies."
-end-
The ALS Association is the only national nonprofit organization fighting Lou Gehrig's Disease on every front. By leading the way in global research, providing assistance for people with ALS through a nationwide network of chapters, coordinating multidisciplinary care through certified clinical care centers and fostering government partnerships, the association builds hope and enhances quality of life while aggressively searching for new treatments and a cure.

Syracuse University

Related Stress Articles:

Early life stress is associated with youth-onset depression for some types of stress but not others
Examining the association between eight different types of early life stress (ELS) and youth-onset depression, a study in JAACAP, published by Elsevier, reports that individuals exposed to ELS were more likely to develop a major depressive disorder (MDD) in childhood or adolescence than individuals who had not been exposed to ELS.
Red light for stress
Researchers from the Institute of Industrial Science at The University of Tokyo have created a biphasic luminescent material that changes color when exposed to mechanical stress.
How do our cells respond to stress?
Molecular biologists reverse-engineer a complex cellular structure that is associated with neurodegenerative diseases such as ALS
How stress remodels the brain
Stress restructures the brain by halting the production of crucial ion channel proteins, according to research in mice recently published in JNeurosci.
Why stress doesn't always cause depression
Rats susceptible to anhedonia, a core symptom of depression, possess more serotonin neurons after being exposed to chronic stress, but the effect can be reversed through amygdala activation, according to new research in JNeurosci.
How plants handle stress
Plants get stressed too. Drought or too much salt disrupt their physiology.
Stress in the powerhouse of the cell
University of Freiburg researchers discover a new principle -- how cells protect themselves from mitochondrial defects.
Measuring stress around cells
Tissues and organs in the human body are shaped through forces generated by cells, that push and pull, to ''sculpt'' biological structures.
Cellular stress at the movies
For the first time, biological imaging experts have used a custom fluorescence microscope and a novel antibody tagging tool to watch living cells undergoing stress.
Maternal stress at conception linked to children's stress response at age 11
A new study published in the Journal of Developmental Origins of Health and Disease finds that mothers' stress levels at the moment they conceive their children are linked to the way children respond to life challenges at age 11.
More Stress News and Stress Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: The Power Of Spaces
How do spaces shape the human experience? In what ways do our rooms, homes, and buildings give us meaning and purpose? This hour, TED speakers explore the power of the spaces we make and inhabit. Guests include architect Michael Murphy, musician David Byrne, artist Es Devlin, and architect Siamak Hariri.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

What If?
There's plenty of speculation about what Donald Trump might do in the wake of the election. Would he dispute the results if he loses? Would he simply refuse to leave office, or even try to use the military to maintain control? Last summer, Rosa Brooks got together a team of experts and political operatives from both sides of the aisle to ask a slightly different question. Rather than arguing about whether he'd do those things, they dug into what exactly would happen if he did. Part war game part choose your own adventure, Rosa's Transition Integrity Project doesn't give us any predictions, and it isn't a referendum on Trump. Instead, it's a deeply illuminating stress test on our laws, our institutions, and on the commitment to democracy written into the constitution. This episode was reported by Bethel Habte, with help from Tracie Hunte, and produced by Bethel Habte. Jeremy Bloom provided original music. Support Radiolab by becoming a member today at Radiolab.org/donate.     You can read The Transition Integrity Project's report here.