A new hypothesis for Parkinson’s: Triggers, Facilitators and Aggravators
Why is it important?
- Novelty 85% 85%
- Proximity 60% 60%
- Deliverability 60% 60%
“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.”
The authors identify three key factors that may be influencing the progression of Parkinson’s:
- “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.
- “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.
- “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.