Discovery of a Potential new target for ALS Drugs to curb protein misfolding!

The once-popular "Ice Bucket Challenge" aims to raise awareness of ALS. This rare disease name amyotrophic lateral sclerosis (Amyotrophiclateralsclerosis, ALS), belongs to neurodegenerative diseases. In the early stage, patients show muscle atrophy, muscle twitches, limb weakness and speech confusion. After 3-5 years of onset, patients often suffer paralysis due to general muscle weakness and die from respiratory failure. Only 10% of patients survive more than 10 years, and very few survive more than 50 years, such as the famous physicist Stephen Hawking.

Most of the causes of ALS are unknown, and only about 10 percent of cases are genetic. It is believed that a variety of interrelated molecular mechanisms, including protein balance, folding and transport dysfunction, excessive neuronal stimulation, oxidative stress, neuroinflammation, etc., contribute to the occurrence of the disease. These disorders lead to the degeneration and death of motor neurons, causing muscle atrophy that gradually spreads throughout the body.

So far, more than 25 genes related to ALS have been identified. Among them, C9ORF72, SOD1, TARDBP and FUS gene mutations were the most common genetic causes of ALS. Other mutations have been found in ANG, VAPB, VCP, SQSTM1, DCTN1, DAO, SETX, ATXN2, OPTN, SCFD1, NEK1, C21ORF2, etc.

Riluzole is the first drug approved by the FDA to treat ALS. Although riluzole extended survival by 3-5 months in clinical trials, it did not repair existing motor neuron damage. Edaravone (Radicava) was approved by the FDA in May 2017 to treat ALS. Its antioxidant effects are believed to alleviate the effects of oxidative stress and may delay disease progression or limit additional damage. In addition, there are symptomatic medications that can be used to relieve the symptoms of ALS.

Recently, According to a new study published in the journal NeurobiologyofAging of "LossofamyotrophiclateralsclerosisriskfactorSCFD1causesmotordysfunctioninDrosophila", Researchers at the University of Malta switched off the SCFD1 gene in fruit flies. By observing the consequences, the researchers revealed how the loss of SCFD1 function triggers ALS symptoms and suggested a potential new drug target for ALS.

SCFD1 has been identified as an associated risk site for ALS in MinE, a large international study involving over 100,000 patients and healthy volunteers with ALS. "The SCFD1 gene is one of the strongest risk factors for ALS patients worldwide," explains Dr. RubenJ.Cauchi, associate professor of neurogenetics at the University of Malta and principal investigator of the latest study. However, the significance of the association between SCFD1 and disease remains unknown. "This large study was able to find genes that were mutated more frequently in ALS patients than in healthy volunteers, but at the same time, the exact link between the genes they found and ALS wasn't clear."

In the latest study, researchers at the University of Malta observed that when the SCFD1 gene was knocked down, adult fruit flies developed dysmotility. A strong knock down of the SCFD1 gene caused the larvae to develop dysmuscular contractions and neuromuscular junctions, which made them appear more rigid and stretched when pupating.

RNA sequencing of larvae with strong SCFD1 knockdown revealed 585 differentially expressed genes. Analysis of the dysregulation pathways found that the most significant downregulation was found in pathways surrounding protein folding or refolding. In past studies, it has been established that misfolding and protein aggregation are signature features of ALS. Inhibiting the ability of motor neurons to fold proteins correctly will increase susceptibility to ALS, so repairing or activating patients' SCFD1 will hopefully slow or stop their disease.

The team believes they are on the right track. Last September, the new drug AMX0035, which had already received conditional approval in Canada, received similar approval in the United States under the trade name Relyvrio after intense lobbying from patient groups. AMX0035 targets protein folding errors. AMX0035 is a proprietary oral combination of two drugs already in use, sodium phenylbutyrate (PB), which inhibits endoplasmic reticulum stress responses and neuronal cell death caused by protein misfolding or mutation, and tauroursodeoxycholic acid (TUDCA). TUDCA has anti-apoptotic and neuroprotective effects. But the combination changed more gene expression than either PB or TUDCA alone.

Reference materials:

[1]RebeccaBorg,AngiePurkiss,RebeccaCacciottolo,etal,LossofamyotrophiclateralsclerosisriskfactorSCFD1causesmotordysfuncti OninDrosophila NeurobiologyofAging, 2023, ISSN0197-4580, https://doi.org/10.1016/j.neurobiolaging.2023.02.005.

[2]vanRheenen,W.,Shatunov,A.,Dekker,A.etal.Genome-wideassociationanalysesidentifynewriskvariantsandthegeneticarchitectur Eofamyotrophiclateralsclerosis NatGenet48, 1043-1048 (2016). https://doi.org/10.1038/ng.3622

[3]https://www.biostock.se/en/2022/12/new-drugs-bring-hope-to-als-patients/

[4]https://www.alzforum.org/therapeutics/relyvrio