Where in the body does Parkinson’s disease begin?
The takeawaySeveral lines of evidence have suggested that Parkinson’s may be caused by a dual-hit to the body: both in brain, and specifically in the olfactory bulb (the part of the brain that processes smell) but also in the gut. The jury is still out about whether this hypothesis is accurate.
Why is it important?This review summarises findings that support a dual-hit hypothesis, but also identifies open questions and inconsistencies which future studies can address directly, in order to settle this essential open question.
Impact Opinion“How Parkinson’s progresses over time is a critical question in the field of PD research. This review provides a timely overview of where the research addressing this issue currently is, as well as asking some key unanswered questions. And this is an important area for the Parkinson’s research community as there are major ongoing clinical trial programmes targetting the toxic form of alpha-synuclein. Therapies that are attempting to remove the toxic form of alpha synuclein have now reached the all important phase II stage, which tests whether the treatment actually works. A better understanding of the role of alpha synuclein in the progression of Parkinson’s would greatly help those clinical trial efforts”
BackgroundAlpha-synuclein is the major known culprit in Parkinson’s: it is normally found in neurons and is thought to be involved in their communication. When it forms harmful clumps, it damages neurons, and is also capable of moving between them, thereby spreading the damage, in a manner similar to that seen by prions – proteinaceous infectious agents. Indeed, some parallels have been drawn between transmission patterns of alpha-synuclein and some forms of the prion condition Creutzfeld-Jacob disease (CJD).
Since neurons are not only present in the brain, but across the whole body, including the lining of the gut, researchers have been trying to map the presence of alpha-synuclein in people with Parkinson’s to understand the way in which it spreads as the condition starts and progresses. If we can trace its very earliest origins, then we may be able to stop its spread. So where does Parkinson’s really start?
The detailsThe dual-hit hypothesis proposes that alpha-synuclein may spread in two major ways – from the olfactory bulb and then across to other parts of the brain, and from the gut, traveling up the vagus nerve and eventually into the brain. The vagus nerve (the vagrant, from the Latin for wandering) is the major nerve that supplies the gut, heart and lungs. Since it was first proposed over a decade ago, several lines of evidence have emerged to support it, but important questions also remain unresolved.
First, the ways in which major neuronal pathways are interconnected in the brain, but also connect the brain to different parts of the body and organs such as the gut and heart would theoretically allow for this pattern of a-synuclein spread. Beyond the theory, preclinical studies have also shown that alpha-synuclein injected into the gut can be found a week later in the brainstem. In people with Parkinson’s, alpha-synuclein can be found in a number of organs including the gut, skin and heart, as well as the brain. If the dual-hit hypothesis is correct then there should be some cases in which alpha-synuclein, in addition to being found in the key brain regions, should be found in the olfactory bulb, and others in which it is only found in the gut (in the periphery). Unfortunately, different groups report inconsistent results in this respect. Some of the difficulties in this research which is performed at autopsy include inconsistencies in the actual methods used to identify alpha-synuclein, and future multi-centre studies will aim to standardize these methods to answer this question definitively.
One of the most important and fascinating sources of support for the possibility that in some people Parkinson’s may start in the gut originates in studying the effects of surgically severing or cutting the vagus nerve which supplies the gut. Prior to the use of antibiotics for the treatment of peptic ulcers, surgery was often performed to cut the vagus nerve. When individuals who had undergone this vagotomy were followed up decades later, two independent studies found this led to a lower risk for Parkinson’s, but a third group reanalyzed some of these data and did not replicate this result. Again, methodological differences confounded the issue. Other intriguing findings include the relatively higher risk for Parkinson’s seen after surgery for appendicitis and antibiotics for peptic ulcers, which could point to a different effect altogether – that of inflammation in the gut which may be triggering the abnormal folding of alpha-synuclein in the first instance.
Next stepsFuture work will focus on developing a consensus in terms of the techniques used to identify alpha-synuclein in different types of tissue, and larger epidemiological studies will help settle open questions such as the true effects of appendectomy.
Where can I learn more?
Hawkes, CH, Del Tredici, K, Braak, H. (2007). Parkinson’s disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol, 33(6): 599-614.