# Project I "Mechanisms of Pathological aSyn Transmission"

> **NIH NIH U19** · UNIVERSITY OF PENNSYLVANIA · 2020 · $520,676

## Abstract

PROJECT I: “Pathological α-Synuclein Transmission and Strains”
PROJECT LEADER: VIRGINIA M.-Y. LEE
Project I Summary/Abstract
Project I, formerly Project III, is renumbered as Project I to improve the flow of the Projects in our re-submitted
new U19 grant entitled “Center On Alpha-synuclein Strains In Alzheimer Disease & Related Dementias” at
the University of Pennsylvania (Penn) Perelman School of Medicine (PSOM) to test the transmission and strain
hypotheses of a-synucleinopathies. Dementia with Lewy bodies (DLB), Parkinson's disease (PD) without and
with dementia (PDD), referred to here as Lewy body (LB) disorders (LBD), all share LB and Lewy neurite (LN)
intra-neuronal pathology comprised of aggregated α-synuclein (aSyn). LBD, PDD and Alzheimer's disease (AD)
with (AD+aSyn) or without LBs (AD-aSyn) are the most common aging related dementias. Moreover, LBD,
AD+aSyn and multiple system atrophy (MSA), characterized by misfolded aSyn in glial cytoplasmic inclusions
(GCIs), are the major neurodegenerative synucleinopathies. This diversity of clinical features and aSyn
neuropathology in brains of neurodegenerative disease patients provides indirect support for the strain
hypothesis wherein pathological aSyn adopts different conformations or strains that account for clinical and
pathological heterogeneity between these disorders. Further, we propose the transmission hypothesis of
aSyn strains to explain the variability in progression of LBD, AD+aSyn and MSA. However, both hypotheses
need rigorous testing. Recently Project I and II investigators collaborated to demonstrate that intrastriatal
injections of recombinant aSyn preformed fibrils (PFFs) into wildtype (WT) mice induced the templated
misfolding and aggregation of endogenous aSyn that spread progressively across the striatal connectome to
form PD-like LBs and LNs followed by dopaminergic (DA) neuron loss in the substantia nigra pars compacta
(SNpc) and motor impairments characteristic of PD. Our key observations have been validated by many other
laboratories and extended to rats and non-human primates (see preliminary non-human primate data in Project
II) thereby supporting the transmission hypothesis. These confirmatory studies also showed that these novel
models recapitulate LBD pathogenesis and will facilitate LBD research. We also have identified distinct aSyn
strains with different conformations and biological activities through the serial in vitro propagation of synthetic
aSyn PFFs generated from recombinant aSyn and we have isolated distinct human LBD, AD+aSyn and MSA
aSyn strains from LBD and AD+aSyn, as well as MSA brains characterized genetically and neuropathologically
by Core C from patients followed by Core B and studied clinically in Projects III and IV thereby collaboratively
linking all U19 Projects and Cores. These studies defined distinct aSyn strains from AD+aSyn and LBD brains
designated as aSyn-LB (LB+LN) and from MSA brains designated as aSyn-GCI. These and other prelimin...

## Key facts

- **NIH application ID:** 10020334
- **Project number:** 5U19AG062418-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** VIRGINIA M LEE
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $520,676
- **Award type:** 5
- **Project period:** 2019-09-30 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020334

## Citation

> US National Institutes of Health, RePORTER application 10020334, Project I "Mechanisms of Pathological aSyn Transmission" (5U19AG062418-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10020334. Licensed CC0.

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