Toxic Protein in Parkinson’s Disease Patients Removed by Steroid from Dogfish Shark

A steroid made by the dogfish shark was synthesized artificially, by a multi-University research team including Cambridge University, and which was found to prevent the buildup of a protein associated with neurodegenerative diseases like Parkinson’s. The lethal protein called alpha-synuclein (α-synuclein) could be a potential target of drug therapy for such neurodegenerative diseases. The newly synthesized steroid was called squalamine and it was found to reduce the α-synuclein clumps that are found in patients with Parkinson’s disease. Functions of Squalamine:

The findings of the study show that squalamine

• prevents the build up of α-synuclein
• eliminates it from the neurons by removing the protein which clings to the the inner wall of nerve cells.

The study was conducted on genetically engineered nematode worm C. elegans, altered to produce human α-synuclein in its muscles. When the worms grow in age, the build up of α-synuclein inside the muscle cells leads to cellular damage and paralysis.

Dr. Michael Zasloff who is the co-senior author of the study and a professor at George Town University said that the researchers found that when squalamine was administered orally to the worms, it prevented the clustering of α-synuclein and limited muscular paralysis within the worms.

In 1993, Dr. Zasloff  discovered the protein in dogfish sharks and in 1995 he synthesized Squalamine. The process that is used to synthesize squalamine does not include the use of any shark tissue. Since then, there have been numerous research conducted on the benefits of using squalamine, with many researchers identifying anticancer as well as anti-viral properties of the protein. This study on the neurological benefits in diseases like Parkinson’s is the first of its kind.

Alpha-synuclein in Parkinson’s

The function of the protein α-synuclein in the healthy brain is unknown but this protein is of great interest to Parkinson's researchers. It is a constituent of Lewy bodies, or protein clumps which are considered the pathological hallmark for Parkinson's disease.

The pathology of alpha-synuclein pathology exists in parts of the brain that are not traditionally related to Parkinson's disease, as it is also found in patients who have no clinical features of Parkinson's. This has fueled many research studies to identify the emerging hypothesis that the disease may affect many areas beyond the substantia nigra in the central nervous system. The diversity of the clinical features associated with Parkinsons has renewed interest in studying about α-synuclein. There are research projects that are aimed at identifying if α-synuclein has potential use as a biomarker of Parkinson’s disease.

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Vaccines are currently being developed to target alpha-synuclein in Parkinson's patients. These vaccines are only in the initial stages of a clinical trial.

Squalamine in Parkinson’s Disease

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There were a series of in vitro experiments to understand the effect of squalamine on the levels of α-synuclein. It was found that

• squalamine was positively charged with increased affinity towards negatively charged membranes that resulted in the α-synuclein being completely removed from membranes that are negatively charged.
• squalamine protected the neuronal cells that were healthy by preventing them from getting attached to masses of α-synuclein.
• Oral administration of squalamine was carried out on C. elegans with Parkinson’s disease. This was found to prevent the toxic α-synuclein clumps from forming.
• The loss of mobility that occurred due to the accumulation of toxic α-synuclein was prevented.

The study was not only successful in the invitro studies but was also found to be successful in the animal studies.

Studies on the abundant abnormal α-synuclein pathology  are gaining in importance as they characterize neuropathological disorders that not only includes Parkinson’s Disease patients but also patients with other neurodegenerative diseases which are collectively called “synucleinopathies.” Various models have been structured to identify the role played by this protein in the pathogenesis of these diseases, identifying pathway ad deciphering the consequences of their accumulation.

Squalamine in Sharks

Animals have developed mechanisms that help defend themselves from environmental microbes in order to survive. There are multiple mechanisms that include humoral as well as cellular responses.

There are a number of low molecular weight antibiotics that have been discovered over the past few years and which are believed to play an important role in the defense against environmental microbes. The identified molecules include lipids, peptides and alkaloids. In the course of discovery, scientists found that the stomach extracts of Squalus acanthias, a shark, was found to exhibit potent antimicrobial activity.

The discovery of squalamine in removing the toxic clumps of α-synuclein could herald in a better method of treatment of Parkinson’s and other associated neurodegenerative diseases. This synthesized protein could be an effective therapy for the disease and aid in better care for Parkinson’s disease patients.

References:

1. Squalamine:An aminosterol antibiotic from the shark - (https://www.michaeljfox.org/understanding-parkinsons/living-with-pd/topic.php?alpha-synuclein)
2. α-Synuclein in Parkinson's Disease - (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC45871/pdf/pnas01102-0225.pdf)
3. Alpha-synuclein and Parkinson's Disease - (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281589/)

Source-Medindia