DETERMINANTS OF PATHOLOGY SPREAD IN SYNUCLEINOPATHIES
- Tim Bartels, United Kingdom
Abstract
Aims
Neuronal aggregates of alpha-synuclein (αSyn) (Lewy bodies and neurites) are a pathological hallmark of Dementia with Lewy Bodies (DLB) and Parkinson’s disease (PD). We investigate here what determines the brain area specificity of αSyn pathology and what leads to the differences in pattern of pathology and neurodegeneration in DLB and PD.
Methods
We use here human brain tissue from 9 different regions and various structural assays to characterize the different functional forms of αSyn dependent on brain region and disease condition. Mechanistically, we then use the neuroblastoma cell line M17D expressing different forms of αSyn and the exposure to pre-aggregated amyloid to investigate what makes pathology spread possible and explains higher resistance of some brain regions over others.
Results
We can demonstrate that DLB and sPD patients exhibit a region-specific reduction of αSyn helical multimers in brain tissue according to the classical Braak staging scheme, indicating their destabilization in the course of the disease. We show here that the main physiological form is not only resistant to time-dependent self-aggregation but also shows increased resistance towards "prion-like" aggregation.
Conclusions
The results indicate the vulnerability of early affected brain regions, the importance of a balance of aSYN multimers and monomers and the functional reserve of different brain regions. A factor governing the stabilization of multimers seems to be lipid composition of the cell specific membranes since transient lipid contact acts as a catalyst for multimer formation, meaning that lipid vesicles might act as a “liposomal chaperone” capable of conferring aggregation resistance to the cytosolic αSyn.