Grants and Contracts Details
Description
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.
Status | Finished |
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Effective start/end date | 6/1/11 → 9/30/16 |
Funding
- National Center for Advancing Translational Sciences
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