Science & Technology (Commonwealth Union) – The idea that Parkinson’s disease might start in the gut has been around for a while. It makes sense, given that the dorsal motor nucleus of the vagus nerve, a brain area often hit early on, is directly linked to the digestive system. But the exact route the disease takes from the gut to the brain has been a bit of a mystery.
This new research shines a light on gut macrophages. These are specialized immune cells, the body’s initial responders, which gobble up and dismantle harmful things. The study shows how these macrophages help toxic proteins get from the gut into the brain.
Researchers found that lowering the number of these gut macrophages reduced the spread of toxic proteins and led to improved motor function in mice. Published in Nature and supported by funding from the Chan Zuckerberg Initiative, the findings point to a promising new therapeutic strategy for Parkinson’s, with the potential to intervene well before motor symptoms emerge.
Earlier studies have shown that 50–90% of people with Parkinson’s experience gastrointestinal issues long before movement problems develop, such as chronic constipation occurring decades prior to diagnosis. Patients are often classified as either “body-first” or “brain-first,” depending on where the disease begins, with the body-first form accounting for roughly two-thirds of Parkinson’s cases.
In the latest research, scientists extracted misfolded alpha-synuclein — the harmful protein linked to Parkinson’s disease — from the brains of individuals who had died with the condition. Minute quantities of this patient-derived protein were then introduced into the small intestines of mice, allowing researchers to trace its movement from the gut to the brain.
The study showed that gut macrophages absorbed the alpha-synuclein and subsequently developed defects in their lysosomes, the cellular structures responsible for breaking down waste.
Researchers also observed that these macrophages sent signals to T cells, key players in the adaptive immune system. Once “programmed” in the gut, the T cells migrated from the intestine to the brain.
Crucially, when scientists reduced the number of gut macrophages before introducing alpha-synuclein into the mice, the accumulation of toxic protein in the brain was significantly lower than in control animals. This points to a potential treatment strategy that targets these immune cells and blocks their passage to the brain.
Going forward, the team aims to further explore how immune activity in the body can adversely affect the brain and whether these pathways can be used to identify new drug targets. They also plan to examine whether inflammatory markers in the blood could serve as early indicators of Parkinson’s disease.
The co-lead author Dr Soyon Hong, Group Leader at the UK Dementia Research Institute at UCL, pointed out that their study indicates that immune cells do not play the role of bystanders in Parkinson’s diseases as these gut macrophages are responding, albeit in a dysfunctional way. Dr Hong further indicated that this points to a chance to ponder about the way they can boost the function of the immune system and these cells, so that they get a response in the correct manner and assist to slow or halt the spread of disease.
Co-lead author Dr Tim Bartels, Group Leader at the UK Dementia Research Institute at UCL, says “Neurodegenerative diseases have slow trajectories over decades. Understanding how Parkinson’s begins in the body could allow us to develop simple blood tests to screen for it, enabling diagnosis long before damage to the brain starts. Having the ability to detect and manage Parkinson’s before it even reaches the brain could have a huge impact for those affected.”
