A Novel Technique to Treat Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that primarily affect middle-aged people. FTD ranks second only to Alzheimer’s disease in terms of dementia prevalence. Both ALS and FTD are caused by neuronal deterioration that is not fully understood.

Dr. Yun-Ru (Ruby) Chen and his team at the Genomics Research Center (GRC), Academia Sinica, have found a new pathogenic mechanism for neuronal degeneration utilizing synthetic peptides. They also discovered that disaccharides can improve neuronal survival and minimize degeneration. The findings provide therapeutic possibilities for the future treatment of these neurodegenerative illnesses. The findings were reported in Science Advances on February 23, 2024.

Patients with ALS endure progressive muscle atrophy and paralysis as a result of motor neuron degeneration in the spinal cord, brainstem, or motor cortex. Scientist Stephen Hawking and former American baseball player Lou Gehrig both have Amyotrophic Lateral Sclerosis. FTD patients, on the other hand, suffer from behavioral deterioration and linguistic problems as a result of neuron loss in the frontal and temporal lobes. Bruce Willis, a Hollywood action star, has revealed that he will retire in 2022 owing to FTD.

Dr. Chen’s research has long been committed to the study of neurodegenerative illnesses caused by protein misfolding. ALS and FTD have distinct clinical symptoms, yet they share numerous pathological traits and genetic variants. Clinical data indicate that more than 90% of ALS and around 70% of FTD patients are sporadic, making it difficult to study the underlying genetic changes associated with the disease. However, in cases involving the same family, the most prevalent genetic mutation for both disorders is an increase in the GGGGCC (G4C2) sequence2 in the C9ORF72 gene.

The first discovery of poly-GR/PR interfering nucleic acid processes in cells

The researchers began by synthesizing poly-GR/-PR peptides with varying repeat numbers. Experiments showed that repeating poly-GR more than 25–30 times impaired neuron survival and damaged cell and nuclear membranes. The study also discovered that the damage was caused by interactions with nucleic acids, which impaired essential biological operations like DNA, RNA, and protein synthesis.

Further tests with cells expressing poly-GR/-PR yielded identical findings, confirming this disease mechanism for the first time. The finding sheds light on the pathogenic process underlying the G4C2 repeat amount in patients.

In conjunction with Dr. U-Ser Jeng’s team at the National Synchrotron Radiation Research Center (NSRRC), the team used Small-Angle X-ray Scattering (SAXS) to investigate the structures of poly-GR and poly-PR. The SAXS data, when combined with computer models, revealed that soft helical structures can emerge when poly-GR repeats surpass 25–30. These findings showed a correlation between the toxicity of soft helical structures and the repeat length of poly-GR and poly-PR.

Sulfated disaccharides mitigate the toxicity of poly-GR/PR

Because mature neurons cannot proliferate, therapies for neurodegenerative illnesses like ALS and FTD aim to increase cell viability. To find potential treatments, the study team employed a library of heparan sulfate compounds developed in the laboratory of Dr. Shang-Cheng Hung, a Distinguished Study Fellow at GRC. Following the screening, a sulfated disaccharide (sucrose octasulfate, SOS) showed the greatest effectiveness in decreasing neuron deterioration in neuroblastoma and ALS iPSC-derived cells.

The scientists also discovered that SOS can offset poly-GR/PR-induced neuronal degeneration, resulting in improved motor behavior in Drosophila and animal models. The results suggest a potential future therapy method for ALS and FTD.

More information: Yu-Jen Chang et al, Sulfated disaccharide protects membrane and DNA damages from arginine-rich dipeptide repeats in ALS, Science Advances (2024). DOI: 10.1126/sciadv.adj0347

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