To the brain through the intestines

Lack of one protein prevented old mice from coping with Parkinson's disease

Polina Loseva, N+1

American scientists have found a mechanism that allows young mice to defeat Parkinson's disease at an early stage. This is the enzyme glucocerebrosidase, with which immune cells break down extracellular clusters of proteins. Young mice have a lot of it, so even "infection" with Parkinson's disease passes in a few months. And old mice don't have enough of it, so their protein lumps settle in the brain. Adding this enzyme to the body can help to cope with Parkinson's disease – not only in mice, but also, probably, in humans. The work was published in the journal Nature Neuroscience (Challis et al., Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice).

One of the main signs of Parkinson's disease is the accumulation of lumps of alpha–synuclein protein in the nervous tissue of the brain. When they are found there in sufficient numbers, it is no longer possible to stop the disease. But some time ago, scientists noticed that long before a person is diagnosed, the first symptoms of the disease appear in the intestines. It is believed that from there accumulations of alpha-synuclein can get into the vagus nerve and reach the brain through it – in mice it takes about a month.

A group of researchers led by Viviana Gradinaru from the California University of Technology decided to understand in detail what exactly is happening in the affected alpha-synuclein intestine. To do this, they worked with adult healthy mice. Since these animals themselves do not suffer from Parkinson's disease, in order to create similar symptoms in them, scientists injected them with precursors of a protein lump – threads, which other alpha-synuclein molecules can then adhere to – directly into the muscular membrane of the duodenum, where many processes of the vagus nerve are located.

3 months after the injection, scientists noticed signs of intestinal dysfunction in the experimental group of animals: the weight of excrement decreased by a quarter, and the time of food movement through the digestive tract, on the contrary, increased by one and a half times.

Then the researchers studied the pathological process in the intestinal wall in more detail. They found that within a week after the injection, inflammation develops in the affected tissue – at least, the concentration of the pro-inflammatory protein IL-6 increases. But clusters of alpha-synuclein aggregates began to appear later. By the 60th day they reached a peak, but by the 120th they not only did not become more, but even less, however, slightly. Therefore, the authors of the work suggested that some way of eliminating protein lumps was launched in the intestines of animals.

The researchers noticed the same effect in the development of other signs of the disease. The mice injected with alpha-synuclein had coordination problems on day 60 (for example, when they had to climb down the perch into their cage), but by day 120 they had disappeared.

Since age is considered one of the main risk factors for the development of Parkinson's disease, scientists assumed that the results of the experiment would be different for older mice. And indeed, they formed more alpha-synuclein in the intestinal wall than in young animals. Both their digestive and motor skills continued to deteriorate 120 days after the injection. In addition, the concentration of dopamine (a neurotransmitter that is in short supply in Parkinson's disease) in the striatum of the brain in elderly animals fell three times in 4 months compared to young mice.

Researchers associate different results for young and old mice with the activity of macrophages – immune cells that perform the work of "scavengers" in the tissue, destroying protein accumulations between cells. They do this with the help of organelles of lysosomes and, in particular, the enzyme glucocerebrosidase. Scientists found two times less of this enzyme in the intestines of elderly animals than in young ones. Apparently, it's just not enough to cope with the lumps of alpha-synuclein in time.

Then the researchers suggested that the addition of glucocerebrosidase may be enough to prevent the development of Parkinson's disease. As a model, they took genetically modified mice, in whose cells alpha-synuclein is constantly produced, and then accumulates in the intestine even more than in old animals after injection. Scientists injected modified mice with a viral vector with the glucocerebrosidase gene and found that their intestinal functions were partially, though not completely, restored.

The authors of the work do not exclude that gene therapy – the introduction of the glucocerebrosidase gene – can be a good way to treat Parkinson's disease in the early stages. And since it is much easier to deliver the gene to the intestine than to the brain, this option may be more realistic than other therapies directly related to the nervous tissue of the brain.

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