Alpha-synuclein buildup in vagus nerve may mark prodromal Parkinson’s | Toxic protein seen early in major nerve linking brain to organs


Overproduction of toxic forms of the alpha-synuclein protein — a Parkinson’s disease hallmark — in the vagus nerve, the longest nerve connecting the brain to the intestines and other key organs, disrupts the autonomic nervous system prior to motor symptom onset, a study in a new rat model reported.

The autonomic nervous system controls involuntary bodily processes, including heart rate, digestion, and breathing. Problems with this system, referred to as autonomic dysfunction, are commonly reported during the so-called “prodromal” stage of Parkinson’s, before motor symptoms that define the diagnosis develop.

Data also showed that toxic alpha-synuclein accumulation in neighboring cells of the vagus nerve activates an inflammatory pathway that damages this nerve, leading to early symptoms like constipation.

These findings shed light on the mechanisms behind prodromal Parkinson’s symptoms and support the use of these rats as a model of prodromal disease. Further research in this model “may contribute to the emergence of effective therapies to delay or prevent the progression of PD [Parkinson’s disease] from the peripheral autonomic nervous system to the [central nervous system],” the researchers wrote.

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Animal study into potential hallmarks of prodromal Parkinson’s

The study, “α-Synuclein induces prodromal symptoms of Parkinson’s disease via activating TLR2/MyD88/NF-κB pathway in Schwann cells of vagus nerve in a rat model,” was published in the Journal of Neuroinflammation.

Nerve cell loss begins during the prodromal period, years before Parkinson’s hallmark motor symptoms are evident. Nonmotor signs of the disease, such as autonomic dysfunction, also may emerge in this period.

Evidence supports constipation, an indication of autonomic dysfunction, “as a diagnostic marker for prodromal PD, which can precede PD motor diagnosis by 15 years or more,” the researchers wrote.

However, the underlying mechanisms of autonomic dysfunction in prodromal Parkinson’s remain largely unknown.

Parkinson’s is characterized by the accumulation of toxic clumps of the alpha-synuclein protein in nerve cells of the brain that produce a major chemical messenger called dopamine, contributing to their death.

Increasing evidence suggests that alpha-synuclein clumps form outside the brain in prodromal or early Parkinson’s, and they can spread to the brain through the vagus nerve, one of the central nerves of the autonomic nervous system.

But how this long nerve contributes to autonomic system problems in prodromal Parkinson’s remains to be determined.

A team of scientists in China hypothesized that toxic forms of alpha-synuclein deposited in the vagus nerve during the prodromal disease stage promoted autonomic dysfunction. To confirm this, they used a virus to promote the production of a toxic form of alpha-synuclein in the vagus nerve of healthy male rats.

About three months after the virus was injected into the vagus nerve, the animals displayed clear signs of digestive problems consistent with autonomic dysfunction, such as slower movements and reduced blood flow in the intestines.

Signs of motor symptoms were detected three months later, as well as a loss of dopamine-producing neurons in the brain.

Collectively, these data suggest that the rats developed early autonomic dysfunction that eventually progressed to motor symptoms with Parkinson’s-like brain damage — reflecting what’s seen in patients and highlighting these rats as an animal model of prodromal Parkinson’s.

Evidence of damage to myelin sheath protecting axons of the vagus nerve

The team also found that, at three months after virus injection, vagus nerve fibers, or axons, showed signs of damage to the myelin sheath and slower conduction of electrical signals. The myelin sheath is a fatty covering that helps nerves rapidly send electric signals along axons to other cells.

Notably, deposits of the toxic form of alpha-synuclein were detected not in axons of the vagus nerve but in nearby Schwann cells, the main cells responsible for making the myelin sheath.

Further experiments showed that toxic alpha-synuclein within Schwann cells activated TLR2, a protein receptor that is normally used to detect infectious invaders inside of cells. TLR2 activation triggered an inflammatory response that caused myelin damage to the vagus nerve.

When the researchers suppressed TLR2 production, there was markedly less vagus nerve damage and dysfunction, and fewer signs of autonomic dysfunction in the rat model.

Still, TLR2 blocking “did not completely reverse the vagus nerve dysfunction induced by [alpha-synuclein], suggesting that the TLR2 inflammatory pathway may be one of the [disease] mechanisms underlying [autonomic dysfunction] in the prodromal PD,” the team wrote.

“Our study revealed for the first time that ultrastructural lesions of the [vagus nerve Schwann cells] were present in the prodromal PD model, which could lead to decreased nerve conduction velocity and reduced intestinal blood flow, and this was directly involved in the development of [autonomic dysfunction],” the researchers added.

While this study focused mainly on digestion-related autonomic dysfunction, the researchers noted a need to also study other autonomic symptoms, like heart problems and sexual dysfunction.



2023-03-13 12:12:47