A new hypothesis for Parkinson’s: Triggers, Facilitators and Aggravators

Original article: Triggers, Facilitators, and Aggravators: Redefining Parkinson’s Disease Pathogenesis, Trends in Neurosciences, October, 2018

The takeaway

A new hypothesis has been put forward which describes three distinct phases in the chain of events leading to Parkinson’s. During these phases, Triggers enable the start of the disease process but are not alone sufficient to cause Parkinson’s. Additional Facilitators, if present, lead to the spread of alpha-synuclein to the brain. Aggrevators exacerbate the spread to brain regions beyond those controlling movement.

Why is it important?

It is a new hypothesis which may help reconceptualise Parkinson’s as an umbrella term for the cluster of different symptoms and disease courses seen in people living with the condition. It could contribute to discovering personalized, stage-specific medical interventions tailored to the individual with the greatest chance of successfully stopping, slowing or even reversing the disease.

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IMPACT

  • Novelty 85% 85%
  • Proximity 60% 60%
  • Deliverability 60% 60%

Impact

“Rather than attempting to develop broad neuroprotective therapies for Parkinson’s – which may have variable effects across individuals who are all at different stages of the condition – the authors of this interesting opinion piece have suggested that targeting influencers (triggers, facilitators, and aggravators) of specific phases of the condition could help in the development of a more personalised approach to the treatment of PD. It is a compelling idea given the variability we see between PwPs with regards to symptoms and progression. The key now, however, is to determine biomarkers for those influencers which can be monitored over time.”

Background

Although Parkinson’s is often discussed as a single condition, it is increasingly acknowledged that under this broad umbrella we have a range of quite diverse symptoms, affecting people at very different ages and in different ways. Experts in the field have put forward a new hypothesis that considers the chain of events that lead to Parkinson’s as we know it, with its range of motor and non-motor symptoms.

The details

The authors identify three key factors that may be influencing the progression of Parkinson’s:

  1. “Triggers”, which are thought to act decades before dopamine loss leads to movement symptoms, and could include exposure to pesticides, head trauma, viral or bacterial infections as well as disturbance in the microbiome in the gut or nose. The ensuing inflammation could at that point trigger the very earliest alpha-synuclein misfolding.

 

  1. “Facilitators”, which are considered factors which take effect over the same period of time after Triggers, and allow their effects to actually impact on the brain. These can be either short-lived, like temporary gastrointestinal inflammation, or permanent. Permanent Facilitators include genetic mutations, whose effects then become particularly harmful. It is important to note that no genetic mutation discovered to date, including LRRK2 and GBA, leads to Parkinson’s with 100% probability, but rather increase the chances of it. As Facilitators, genetic mutations can interact with Triggers, for example a LRRK2 mutation can reduce immune defense against bacteria, which in turn can trigger a cascade of greater inflammation in key regions such as the gut, and then on to alpha-synuclein misfolding and aggregation.

 

  1. “Aggravators” refer to factors that increase the spread of alpha-synuclein between neurons to different parts of the brain as Parkinson’s continues to evolve. These factors can speed up the loss of neurons due to impaired autophagy, or increase neuroinflammation due to the responses of other cells such as glia.

The authors propose that depending on where, in this timeline, a person with Parkinson’s is at the time when a medical intervention, or entry to clinical trial is considered, different therapies are likely to succeed.

Next steps

The authors also highlight many open questions. If this model is supported by more evidence, important questions will focus on finding the most potent triggers, considering the public health implications, and using existing trials to collect such data, to distinguishing between different patient subgroups and identify responders.

Related work and trials

Summary recording

Original article: Johnson, ME, Stetcher, B, Labrie, V, Brundin, L, Brundin, P. October, 2018. Triggers, Facilitators, and Aggravators: Redefining Parkinson’s Disease Pathogenesis.
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