A microscope image of human induced motor neurons that are labeled with a motor neuron marker HB9 in green and a neuron marker TUJ1 in purple to illustrate ALS or Lou Gehrig’s disease
Human induced motor neurons that are labeled with a motor neuron marker HB9 in green and a neuron marker TUJ1 in purple [Ichida Lab, USC].

Two studies led by the University of Southern California (USC), Los Angeles, show reduction of neurodegenerative activity in preclinical research models of amyotrophic lateral sclerosis (ALS) using two different treatment routes to target the life-threatening condition.

The researchers, led by USC stem cell scientist Justin Ichida, believe that their findings could lead to new and much needed treatments being developed for this disease.

ALS, also known as Lou Gehrig’s disease, is a neurodegenerative disease with a fast progression that is characterized by motor neuron loss. In most cases, paralysis and death occur within two to five years of diagnosis. Developing an effective treatment has proved difficult, not helped by a range of different causative genetic pathways.

Many patients with ALS have a rare genetic cause for their condition and while therapies could potentially be targeted to individual mutations, the fast moving and rare nature of the disease makes developing this type of therapy difficult.

“A minority of patients have a variety of genetic causes of ALS that can be inherited within families, and a majority have what is known as ‘sporadic’ disease because its causes are unknown,” said Gabriel Linares, a postdoc in the Ichida lab and a co-first author on both studies, in a press statement. “This makes it a difficult challenge to find one treatment that will work for all patients with ALS.”

The first study, published in Cell Stem Cell last week, made use of a public bioinformatics database known as Connectivity Map, developed by the Broad Institute of Harvard and MIT, to find potential new treatments for sporadic ALS.

They discovered that suppressing the activity of the spliceosome-associated factor protein, encoded by the SYF2 gene, helped halt the symptoms of ALS in cell lines in the lab and in a model mouse (TDP-43) of the disease. In the mice, neurodegeneration, neuromuscular junction loss, and motor dysfunction were all significantly improved.

“What’s really exciting is that SYF2 suppression improved symptoms and pathology related to a protein called TDP-43, which can become toxic and is implicated in close to 97 percent of cases of ALS,” said Yichen Li, a postdoc in the Ichida Lab and co-author on both studies.

In the second study, published today in Cell, the research team found that inhibiting the activity of a different protein, this time PIKFYVE kinase, also had beneficial effects in ALS cell lines and in fruit flies, roundworms, and a mouse model of the disease.

Similar to the first study, the team showed promising results, with reduced neurodegeneration, improved motor function and increased life expectancy seen in the animal models when PIKFYVE was inhibited using the drug apilimod, as well as genetic and RNA-based approaches.

The scientists think that these improvements were triggered by the treatment stimulating motor neurons to clear toxic proteins through a process of exocytosis, where fat based ‘bubbles’ envelop and transport waste build-up to the wall of the cell to improve function and stop cellular breakdown.

“We were able to pinpoint precisely how PIKFYVE inhibition mitigates neurodegeneration, which is important for informing the development of new targeted treatments,” said Shu-Ting (Michelle) Hung, a PhD student in the Ichida Lab and co-author on both papers.

Although this research is still at an early, preclinical stage, the two studies show promise for developing new and more effective therapies for this devastating disease. “Our discoveries bring us closer to achieving our big picture goal: finding treatments that can be broadly effective for all patients who suffer from ALS,” said Ichida.

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