Parkinsonism and intestines
The association of alpha-synuclein protein with Parkinson's disease was found
Alpha-synuclein protein aggregates originating in the intestine may play a key role in the development of Parkinson's disease, writes IOS Press (Targeting Alpha–Synuclein in the Gut May Slow Down Parkinson's Disease).
Article by Denise et al. Gastrointestinal Immunity and Alpha-Synuclein is published in the Journal of Parkinson's Disease – VM.
The researchers are testing the hypothesis that by acting on the enteral nervous system with a compound that can inhibit intracellular aggregation of alpha-synuclein, they can restore intestinal function in the short term and possibly slow down the progressive deterioration of the central nervous system for a long time.
"There is increasing evidence that Parkinson's disease can begin in the intestine," explains senior author Michael Zasloff, MD. – The concept is that aggregates of the alpha-synuclein protein, which are believed to play a key role in the disease, arise in the enteral nervous system and travel along peripheral nerves to the central nervous system, where they eventually cause inflammation and destruction of parts of the brain. Therefore, targeting the formation of alpha-synuclein aggregates in the enteric nervous system can slow down the progression of the disease."
Alpha-synuclein is one of the protective proteins produced by intestinal nerves when they encounter infections. For example, in children with acute bacterial infections of the gastrointestinal tract, intestinal nerves produce alpha-synuclein. Researchers have shown that in children who have undergone intestinal transplantation and are predisposed to gastrointestinal diseases, intestinal neurons begin to produce alpha-synuclein during acute viral infections, protecting nerve cells for a long time. Inside the nerve cell, alpha-synuclein can capture invasive viruses and disrupt their replication. It can also attach to small vesicles containing neurotransmitters and be released from the nerve cells with which they move. Once outside, it can attract protective immune cells from surrounding tissues.
"Recent data from our laboratory and others demonstrate that alpha-synuclein is induced in conditions of viral and bacterial infection and performs an immune function, protecting the enteral nervous system, alerting the adaptive immune system and warning the central nervous system about an infectious agent in advance," said first author Denise Barbut. – In conditions of chronic infections of the gastrointestinal tract or intestinal barrier function disorders, when the expression of alpha-synuclein exceeds its removal, neurotoxic aggregates of alpha-synuclein form damaging aggregates in the enteral nervous system that enter the central nervous system."
To determine whether targeting alpha-synuclein in intestinal neurons can help patients with Parkinson's disease, Dr. Barbut, Dr. Zasloff and his colleagues are currently conducting clinical trials with a compound called ENT-01. ENT-01 is a synthetic derivative of squalamine, a compound originally isolated by Dr. Zasloff from toothfish bile. It displaces alpha-synuclein from the membranes of nerve cells and restores the normal electrical activity of intestinal neurons. Researchers completed a phase 2a study for 50 patients (RASMET) on patients with Parkinson's disease in 2018. More than 80% of the participants had constipation, which is a common symptom of Parkinson's disease, thanks to the drug.
According to Dr. Barbut, "the RASMET study demonstrated that the enteral nervous system is not irreversibly damaged in patients with Parkinson's disease, despite long-standing constipation, which may indicate the opposite. We believe this is the first demonstration of reversing the neurodegenerative process in humans." In addition to bowel symptoms, possible benefits have also been observed for motor and non-motor symptoms such as hallucinations, depression, and cognitive function.
Currently, a double-blind placebo-controlled phase 2b (KARMET) study involving 100 people is being conducted, evaluating the effect of oral ENT-01 tablets on constipation and neurological symptoms.
Parkinson's disease is a slowly progressive disorder that affects movement, muscle control and balance. This is the second most common age-related neurodegenerative disease, affecting about 3% of the population aged 65 years and up to 5% of people over 85 years.
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