# Propagation of Lewy pathology in Parkinson's and related disorders

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $473,964

## Abstract

The accumulation of misfolded proteins represents a common pathological mechanism of most major
neurodegenerative disorders. Neuronal inclusions comprised of aggregated α-Synuclein (aSyn), known as
Lewy bodies (LBs) and Lewy-neurites (LNs), represent a key histopathological feature of Parkinson's disease
(PD) and a family of related disorders known as synucleinopathies, most notably Dementia with LBs (DLB).
LBs are also a prominent feature in nearly half of Alzheimer's disease subjects. Mutations and amplifications in
the SNCA gene encoding aSyn also cause familial forms of PD. Although a large body of histological and
genetic evidence firmly indicate a correlation between aSyn accumulation and disease, it remains unclear how
aSyn pathology actually forms and subsequently contributes to disease. We and others recently demonstrated
that minute quantities of recombinant or patient-derived aSyn aggregates can catalyze the formation of toxic
LBs/LNs in cultured neurons and healthy non-transgenic mice. In both human PD and animal models, this
“seeded” aSyn pathology progressively propagates and spreads to neuroanatomically connected regions,
reminiscent of prion diseases. Importantly, animals with LBs/LNs recapitulate the cardinal features of PD,
including progressive loss of dopamine-producing neurons and locomotor deficits.
This R01 renewal addresses several key biological questions posed by our earlier findings and combines novel
molecular, in vivo, and computational tools to further understand how LBs/LNs form, propagate, and ultimately
contribute to neurodegeneration and neurological symptoms. Aim 1 will identify at the neuron subtypes that
develop LBs/LNs following inoculation with misfolded aSyn. By combining traditional histological methods with
FACS-assisted single-neuron RNAseq, we will determine the molecular signatures associated with
subpopulations that are vulnerable or resistant to LBs/LNs formation. Aim 2 will examine how PD genetic risk
factors reported in the literature intersect with aSyn pathobiology, by testing the effect of knock-down or knock-
in of individual genes on the formation of seeded pathology and neuronal survival. Candidates that significantly
alter either will be confirmed in vivo using knock-out/knock-in mouse lines. Lastly, Aim 3 will integrate our
molecular, genetic, and in vivo experimental data together with publicly available connectivity and gene-
expression atlases to interrogate the mechanisms of pathological spread. Using recently developed
mathematical approaches to describe infectious agent spread, we will develop in silico models to understand
aSyn pathology formation and spread. Completion of these studies should provide valuable insights into the
potential mechanisms by which aSyn contribute to the progression of PD and related disorders. Increased
understanding of the pathogenesis of this and related synucleinopathies should ultimately result in earlier
detection and disease-modifying therapies for th...

## Key facts

- **NIH application ID:** 10347322
- **Project number:** 5R01NS088322-07
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Kelvin C Luk
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $473,964
- **Award type:** 5
- **Project period:** 2015-03-13 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10347322

## Citation

> US National Institutes of Health, RePORTER application 10347322, Propagation of Lewy pathology in Parkinson's and related disorders (5R01NS088322-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10347322. Licensed CC0.

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