According tomedia New Atlas, there have been previous hypotheses that the toxic protein clumps that cause Parkinson’s disease begin to accumulate in the intestines before entering the brain. A new paper, published recently in the journal Nature Neuroscience, is providing new evidence for this hypothesis. The study, led by scientists at the California Institute of Technology, identified a specific enzyme that prevents these proteins from initially gathering in the gut.
The main pathological marker of Parkinson’s disease is the death of progressive cells in the brain’s dopamine secretion neurons. It is thought to be caused by the Louis body, a toxic cluster of proteins called alpha-synaptic nucleoproteins.
Around 2000, German scientist Heiko Braak published a series of controversial studies. These studies suggest that the destructive Louis body first forms in the intestines and then enters the brain through the vagus nerve. Braak’s hypothesis is still divisive, but many recent studies have begun to build a wealth of evidence to support it.
A major study last year showed in mice how these bodies move from the intestines to the brain. Importantly, the study also found that cutting off the vagus nerve could effectively prevent the spread of these toxic proteins from the intestines to the brain. The new study, by scientists at the California Institute of Technology, looks at better the mechanisms by which these proteins move from the intestines to the brain.
The first phase of the new study involved injecting pre-formed alpha-synaptic nucleoprotein aggregates into the intestinal walls of mice to track the development of these protein clusters. Experiments have shown that these Louises can move from the intestines to the brainstem. Interestingly, the researchers noted that although alpha-synaptic nucleoprotein clusters developed similarly in young and older mice, only older mice developed subsequent movement disorders and gastrointestinal diseases. So, what causes these fundamental differences in symptoms between these older animals?
“As we get older, we become less efficient at dealing with pathogens or misfolded proteins,” said Colin Challis, lead author of the new study. “
Some of the more interesting studies of Parkinson’s over the past few years have found that an enzyme called glucancephalethin prosasease (GCase) plays a major role in helping to identify clusters of alpha-synaptic nucleoproteins. Subsequent brain anatomical studies showed a lower level of GCase in the late Parkinson’s disease.
The new study, based on the relationship between age, GCase levels and Parkinson’s symptoms, first determined that GCase gastrointestinal endocrine levels were lower in older mice. It is assumed that a decrease in age-related GCase levels exacerbates pathological symptoms produced by these intestinal-derived clusters of alpha-synaptic nucleoproteins. The hypothesis that gene therapy stimulates the intestinal tract to produce GCase has been somewhat validated. The increase in this enzyme level in the intestine does restore intestinal function and reduces the accumulation of alpha-synaptic nucleoprotein clusters in intestinal neurons.
Viviana Gradinaru, author of the new study, explained: “The genetic mutation that encodes GCase is a risk factor for Gosheand’s and Parkinson’s disease. Our study showed that the gene could be transported by adeno-related viruses to save stomach symptoms in mice, and stressed that in addition to the brain, peripheral neurons are also important targets for the treatment of Parkinson’s disease. “
Published studies do show that the lack of GCase alone is not sufficient to cause alpha-synaptic nucleoprotein aggregation to reach clinically apparent Parkinson’s disease. Conversely, lower age-related GCase function seems more likely to promote the pathological processes that cause the disease, thus adding convincing evidence to the intestinal-brain hypothesis of Parkinson’s disease.
The new study is published in the journal Nature Neuroscience.