How alpha-Synuclein misfolding promotes tau pathology in ADRD

摘要

Abstract The parent award to this Administrative Supplement for AD and ADRD research studies alpha-Synuclein (aSyn) oligomerization in great biophysical detail, using state-of-the-art techniques (fluorescence lifetime FRET, 19F-NMR and TIRF microscopy). Here, we will use these same techniques to understand interactions between aSyn and tau. These data will provide critically important insights into the pathological aSyn/tau interaction that contributes to co-morbidities of various ADRD proteinopathies, including LBD and FTLD. This extension of the original research—which will propel our groups from synucleinopathy to tauopathy research—is quite straightforward, requiring no new materials or methods, but answering exciting new questions. Neurodegenerative diseases are classified based on their predominant proteinopathy (e.g. tauopathies or alpha-synucleinopathies). In tauopathies, misfolded tau (e.g. oligomers, PHF, and NFTs) commonly presents with a comorbid proteinopathy that differs across AD and ADRDs with the severity of co-morbidity directly associated with an adverse prognosis. Ignoring these comorbid proteinopathies likely impedes our understanding of disease pathogenesis. In a recent clinical study comparison, alpha-synuclein (aSyn) comorbidity in AD was described as an important biological subgroup of LBDs. This co-morbidity spans a broad distribution of disorders, even being present in unimpaired aging. Specific to AD, aSyn-rich Lewy Bodies (LB) were observed in the majority of sporadic AD cases (around 60%), familial AD cases (over 60%), and AD cases with Down syndrome (over 50%). Conversely, AD neuropathology appears to contribute to the emergence of dementia in PD and DLB; potentially acting synergistically with aSyn to spread aSyn associated pathology. The hypothesis motivating this work is that the co-morbidity of tau and aSyn pathology in AD and related dementias, including LBD and FLTD, is directly associated with tau’s propensity to interact with aSyn in early- stage oligomeric complexes that form before insoluble fibrillar aggregates. In this supplement, we will test the specific hypothesis that early-stage aSyn oligomers fundamentally alter tau structural biophysics in the cell, and that these changes are an important determinant (and hence target) in pathology. No biophysical data yet exists about how aSyn and tau co-mingle in early stages of misfolding in cells, before fibrils form, nor how those interactions increase toxicity of the aggregates. The parent grant uses our previously establish fluorescence lifetime FRET biosensors to focus on homo-oligomeric interactions (e.g. aSyn-aSyn) in toxic, non-fibrillar oligomers that cause synucleinopathies. In this Supplement, we will use our biosensors to define the biophysical basis for how hetero-oligomeric interactions form between aSyn and tau in tauopathies, how these interactions lead to co-oligomerization, and how they impact tau pathology.