Researchers at Syracuse University say they are making headway in understanding the disease mechanisms of amyotrophic lateral sclerosis (ALS), also known as motor neurone disease or Lou Gehrig’s disease.

Research is being led by Syracuse University professor of biology, chemistry and interdisciplinary neuroscience Carlos A. Castaneda alongside postdoctoral chemistry researcher Thuy Dao. The pair are investigating the molecule ubiquitin, which targets obsolete proteins in cells and was shown to eliminate drops of the protein-encoding gene Ubiquilin-2 (UBQLN2) in solution. Mutations of UBQLN2 have previously been shown to cause ALS and various forms of dementia, including frontotemporal dementia (FTD).

Ubiquitin and UBQLN2 are part of what Castaneda calls a ‘quality-control mechanism’, which ensures proteins maintain their proper levels during a cell’s lifespan. Any disruption to protein homeostasis usually impairs neuronal development and function.

“Defects in protein recycling contribute to neurodegeneration,” Castaneda said. “The more we understand UBQLN2’s biological functions, specifically, how its mutations lead to ALS, the better we can develop new therapies.

“UBQLN2 is found in motor neuron inclusions of patients with ALS. 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 research has been supported by the ALS Association, and is the subject of a paper published in the journal Molecular Cell. Other study authors include members of J. Paul Taylor’s research group from St. Jude Children’s Research Hospital and the Howard Hughes Medical Institute, and members of Heidi Hehnly’s lab at SUNY Upstate Medical University.

During their research the team demonstrated that UBQLN2 is a stress granule (SG). These are formed when a eukaryotic cell is under stress, causing certain proteins to combine with RNA. Though not abnormal, dysregulation or persistence of SGs can lead to disease.

“We want to understand the mechanisms that trigger motor neurons to degenerate in ALS,” Castaneda said. “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.

“This gives our work potential ALS relevance, since mutations in UBQLN2 might lead to defects in either SG assembly, or SG disassembly, or both.

“UBQLN2 is like a shuttle, ferrying misfolded proteins to the cell’s protein-recycling plant. 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.”

Castaneda has plans to continue investigating UBQLN2, specifically looking into its interaction with other RNA-binding proteins such as TDP-43, which is found in 97% of patients diagnosed with familial or sporadic ALS.

ALS is a degenerative disease in which neurons in the body are attacked, causing their corresponding muscles to weaken and die. Patients gradually lose the ability to speak, swallow, move and eventually breathe. It most commonly occurs in people between the ages of 40 and 70, and is 20% more likely to occur in men. However, researchers have not yet determined the environmental or genetic causes of the condition.

According to Castaneda, muscle weakness or stiffness is the most common early 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,” Castaneda said. “The average survival time is three years after diagnosis.”

There is currently no cure for ALS, though the medications riluzole and radicava significantly extend patients’ lives. The former was created by Sanofi and helps to delay ventilator-dependence or tracheostomy in patients, while the latter helps to slow the decline of physical capability in patients by a third.

Riluzole has been approved by the National Institute for Health and Care Excellence (NICE), while radicava has received approval from the Pharmaceutical and Medical Device Agency (PMDA) in Japan. Both drugs are FDA-approved.