Credit: Imperial College London
Scientists at a German research centre have found that “α- synuclein” , a protein involved in a series of neurological disorders including Parkinson's disease (PD), is capable of travelling from brain to stomach, following a specific pathway. The study , carried out in rats, sheds new light on pathological processes that could underlie disease progression in humans.
α- synuclein occurs naturally in the nervous system, where it plays an important role in synaptic function. However, in PD, dementia with Lewy bodies and other neurodegenerative diseases termed "synucleinopathies", this protein is accumulated within neurons, forming pathological aggregates. Distinct areas of the brain become progressively affected by this condition. The specific mechanisms and pathways involved in this widespread distribution of α- synuclein pathology remain to be fully elucidated. Clinical and experimental evidence suggests however that α- synuclein - or abnormal forms of it - could "jump" from one neuron to another and thus spread between anatomically interconnected regions.
α- synuclein lesions have also been observed within neurons of the peripheral nervous system, such as those in the gastric wall. In some PD patients, these lesions were detected at early disease stages. "Based on these intriguing observations, it has been hypothesized that the pathological process underlying Parkinson's disease may actually start in the gastrointestinal tract and then move toward the brain", says the Senior researcher of the study. "Our present approach was to look at this long-distance transmission of α- synuclein from the opposite perspective, investigating the possibility that α- synuclein may travel from the brain to the gut.“
The scientists tested this hypothesis in a laboratory study. With the help of a tailor-made viral vector they triggered production of human α- synuclein in rats. The virus transferred the blueprint of the human α- synuclein gene specifically into neurons of the midbrain, which then began producing large quantities of the foreign protein. It has been found that some forms of PD are associated with an overproduction of α- synuclein. In this study, the model mimics events of likely relevance to humans.
Tissue analysis have revealed that, after its midbrain expression, the protein was capable of reaching nerve endings in the gastric wall. Further work in the laboratory established the precise pathway used by human α- synuclein to complete its journey from the brain to the stomach. The protein first moved from the midbrain to the "medulla oblongata", the lowest brainstem region; in the medulla oblongata, it was detected within neurons whose long fibers form the "vagus nerve". Fibers of the vagus nerve connect the brain to a variety of internal organs; travelling within these fibers, human α- synuclein was ultimately able to reach the gastric wall about six months after its initial midbrain expression. Progressive accumulation of human α- synuclein within gastric nerve terminals was accompanied by evidence of neuronal damage.
The study shows that α- synuclein is able to travel quite far through the body, passing from one neuron to another and using long nerve fibers as conduits. The findings of the study does not rule out the possibility that diseases associated with α- synuclein may originate in the gut, which may happen in some patients. The study results indicate however, that if pathological alpha-synuclein is detected outside the brain, this does not necessarily mark the site where the disease started.
The study also reveals a preferential route of α- synuclein transmission via the vagus nerve. The vagus nerve is composed of two kinds of fibers: 10-20% of fibers are "efferents" whereas the remaining 80-90% are "afferents". Efferent fibers are projections of motor neurons that control the gut's motility. In contrast, afferent fibers relay sensory input from the gut to the brain. For its journey from the brain to the stomach, α- synuclein only used the less abundant efferent vagal projections.
The study shows that transmission of α- synuclein is not just a matter of anatomical connections. Certain neurons appear to have a particular propensity to take up, transfer and accumulate α- synuclein .We don't know the precise mechanisms underlying this selective neuronal behavior. It is likely, however, that these mechanisms could explain why certain neuronal populations and brain regions are particularly susceptible to α- synuclein pathology.