Synuclein Seed Detection in Synucleinopathies

Synucleinopathies, including Parkinson disease (PD), Dementia with Lewy bodies (DLB), and Multiple System Atrophy (MSA), involve abnormal accumulation of the protein alpha-synuclein. There is increasing evidence that synuclein itself plays a role in the propagation of pathology seen in these diseases. Transcellular movement of misfolded synuclein aggregates or “seeds” is thought to occur. These synuclein seeds then serve as templates for further misfolding of endogenous synuclein and lead to a cascade of spreading pathology throughout the brain. Further, in classic prion literature, conformational or “strain” differences in the cellular prion protein have been shown to exist and are thought to underlie the presentation of different prion syndromes. Synuclein may function in this fashion in disease states. To investigate this idea, we have developed a novel cell-based assay for detection and quantification of synuclein seeding activity. This system has worked exceedingly well for detection of seeding from recombinant synuclein and demonstrates specificity for synuclein and picomolar sensitivity. We will use this system to investigate seeding activity within the brains of patients with synucleinopathies such as PD and MSA. Seeding activity in this assay, as well as biochemical and antibody-based methods, will be used to determine whether strain differences exist between seeded aggregates of synuclein from patients with different synucleinopathies. Understanding the transmission of pathological aggregates in synucleinopathies will be useful not only from the perspective of biomarker development, but also for the creation of novel and disease-specific therapeutic avenues to block propagation of pathology.