For years, researchers have believed that clumps of the protein alpha-synuclein, known as Lewy bodies, were the primary cause of Parkinson’s. Consequently, diagnoses have focused on detecting these clumps, and if they were not visible, a Parkinson’s diagnosis was not made.

However, a discovery challenges this view. Scientists have now identified another, previously invisible marker of the disease in cases where autopsies did not reveal Lewy bodies.

"It turns out that patients without visible Lewy bodies have small accumulations of alpha-synuclein that are not large enough to form a classic Lewy body. Yet, these mini-clumps still cause disease in the body. This suggests that Parkinson’s may develop in different ways and that Lewy bodies may not be the primary cause," explains Nanna Møller Jensen, a postdoc at Aarhus University.

Research unveils invisible disease mechanisms

Together with colleagues—including researchers from Australia—Nanna Møller Jensen has developed a specialized staining method, PLA, which can detect small accumulations of alpha-synuclein. This method makes the invisible visible, providing a deeper understanding of the disease.

"Our research shows that two Parkinson’s patients can have different disease mechanisms in the brain. One patient may develop classic Lewy bodies, while the other only accumulates miniature clumps of alpha-synuclein. This discovery makes the disease far more complex, as these mini-clumps accumulate in multiple brain regions and different types of nerve cells—even in patients with Lewy bodies," she continues.

Notably, small clumps have been found in brain regions without Lewy bodies, suggesting that these accumulations may appear earlier in the disease's progression.

"Our research confirms that the disease likely develops long before Lewy bodies form, and with the PLA method, we can now detect these mechanisms at an earlier stage than ever before," emphasizes Nanna Møller Jensen.

New possibilities for early diagnosis

Another key discovery is that alpha-synuclein clumps are not only found in the brain but also spinal fluid, skin samples, and possibly even blood. This has led Jensen and her colleagues to test the PLA method on these samples in international collaborations.

If the results are promising, the next step will be to explore whether the method can measure the effectiveness of new Parkinson’s treatments.

"If it turns out that the miniature clumps—rather than traditional Lewy bodies—are the real drivers of disease progression, then our treatments should be targeted at these clumps. This finding could be crucial for how we diagnose and treat Parkinson’s in the future," concludes Nanna Møller Jensen.

The article is based on two the following articles:

• "MJF-14 proximity ligation assay detects early non-inclusion alpha-synuclein pathology with enhanced specificity and sensitivity" (published in npj Parkinson's Disease)

• Abundant non-inclusion α-synuclein pathology in Lewy body-negative LRRK2-mutant cases (Pre-print on bioRxiv)