Study Rationale:
Parkinson's disease is caused by the buildup of a protein called α-synuclein in brain cells, and, in most patients, this protein forms large clumps called Lewy bodies that we can see under a microscope. Patients with a genetic form of Parkinson's disease caused by LRRK2 gene mutations often don't have these visible Lewy bodies, making scientists wonder if the same disease process is happening, but our recent laboratory tests have discovered that even LRRK2 patients without Lewy bodies still have small clumps of α-synuclein protein in their brains. This study will determine whether these protein clumps can spread disease from cell to cell, which could explain how the disease progresses in all patients regardless of their genetic background.
Hypothesis:
We hypothesize that small α-synuclein protein clumps found in LRRK2 Parkinson's disease patients without visible Lewy bodies can spread between brain cells, similar to the large protein clumps in typical Parkinson's patients.
Study Design:
This international study will use brain tissue samples from patients with LRRK2 mutations to compare two different approaches for detecting α-synuclein protein abnormalities: three laboratories will test for small α-synuclein protein clumps using different detection methods, while a specialized company will measure the ability of α-synuclein protein to spread between cells. We will examine samples from 25 patients with various LRRK2 mutations from 5 brain banks globally to determine the link between small α-synuclein protein clumps and their ability to spread disease.
Impact on Diagnosis/Treatment of Parkinson’s disease:
This study will standardize α-synuclein detection methods across laboratories, potentially improving early diagnosis of Parkinson's disease before symptoms appear. By clarifying the relationship between protein clumps and disease-spreading activity, the research will identify new targets for treatments that could slow or prevent disease progression.
Next Steps for Development:
If successful, the next steps will include developing disease indicators for fluid from spinal tap that detect small α-synuclein clumps in living patients and evaluating how these protein clumps spread through different brain regions. These advances could enable earlier diagnosis and targeted therapies before irreversible brain damage occurs.