Effect of fibril structure on the disease pathogenesis of a novel alpha-synuclein strain

About This Grant

PROJECT SUMMARY Central synucleinopathies have historically been categorized based on the type of neuropathological inclusions found in the brain at the time of autopsy, with glial cytoplasmic inclusions (GCIs) defining multiple system atrophy (MSA) and Lewy bodies (LBs) defining the Lewy body diseases – Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies. Cryo-electron microscopy (cryo- EM) studies determining the high-resolution structures of the α-synuclein (α-syn) fibrils found in these lesions have shown that misfolded α-syn adopts distinct structures, or conformations, in these two groups of disorders. This has been critical for validating the strain hypothesis, or the idea that different protein structures are associated with discrete biological consequences in a patient. However, an increasing number of studies indicate that multiple, and sometimes novel, α-syn strains can co-exist in an individual patient, complicating efforts to understand the molecular underpinnings of disease. For example, cryo-EM studies on atypical MSA patients with limbic predominant neuronal cytoplasmic inclusions resulted in the discovery of a Lewy-MSA hybrid fold of α-syn, suggesting that previously unidentified α-syn strains contribute to disease heterogeneity. This finding is consistent with our recent isolation of an undescribed α-syn strain from a PDD patient sample exhibiting biological properties that are distinct from both the MSA and LB strains. Stemming from the increasing identification of new α-syn strains in patient samples, there is a growing need to understand the specific biological consequences of each strain on disease pathogenesis. The long-term goal of our research is to use our understanding of α-syn disease biology to successfully develop diagnostics and therapeutics for synucleinopathy patients. Our objective in this application is to determine how the molecular structure of a recently isolated α-syn strain impacts the route of spread to clinical target areas in the brain, ultimately determining the clinical presentation of disease, including dementia. Building on this discovery, our hypothesis is that structurally and biologically distinct α-syn strains exhibit critical differences in disease pathogenesis in vivo. Our innovative approach will capitalize on our expertise investigating the MSA α-syn strain, which will serve as a unique opportunity to directly compare two distinct patient-derived strains to determine the effect of fibril structure on disease biology. In Aim 1, we will use serial passaging to further isolate and investigate novel α-syn sub-strains from patient sample PDD1 and will use cryo-EM to resolve the new fibril structure(s). In Aim 2, we will assess neuroinvasion following peripheral injections using the PDD1 and MSA strains to determine how structural differences in α-syn fibril structure impacts disease pathogenesis. This work is significant because we will generate the deep phenotyping needed to enable widespread identification of the novel PDD sub-strain, as well as determine the role of strain dynamics on the structure-phenotype relationship in synucleinopathies.