# Investigating the interplay between polymorphic α-syn fibril conformation and cell-dependent pathology

> **NIH NIH R21** · DREXEL UNIVERSITY · 2024 · $414,191

## Abstract

Project Summary
Conformational variations in α-syn fibrils are proposed to be implicated in the emergence of distinct diseases
within synucleinopathies, including Lewy body dementia (LBD), Parkinsons’s disease (PD), and multiple system
atrophy (MSA), suggesting a molecular fingerprint closely connected to clinical diagnosis. However, the
mechanisms underlying the appearance of these disease-specific conformations and their impact on the
progression of distinct pathologies in synucleinopathies remain largely unclear. Motivated by the existing
knowledge gap between structural polymorphism and disease entities, the goal of this proposed research is to
investigate how α-syn pathology propagates in a disease-specific manner, by focusing on the molecular
interactions between α-syn fibril structures and diverse cellular environments. To achieve this, we will employ a
multidisciplinary approach based on the combination of biophysical approach, molecular biology, and human
organ-on-a-chip technology. Building upon our complementary expertise in neurodegenerative amyloid fibril
research and human organ-chip development, we will produce various forms of α-syn fibril seeds, characterize
their conformations, and investigate their functions in human vascularized brain-on-chips with an unprecedented
physiological realism. The central hypothesis posits that the membrane-mediated polymorphisms of α-syn fibrils
are a key factor in the emergence of the distinctive pathological features of synucleinopathies, including LBD
and PD, through the molecular interactions between α-syn fibrils and cellular membranes. These interactions
are significantly influenced by the distinct conformations of α-syn fibrils and the varying membrane conditions
found in different types of brain cells. This hypothesis will be tested by pursuing three specific aims: 1) Generate
the polymorphic α-syn fibrils in the presence of various physiologically relevant membranes and characterize
their functional properties; 2) Create microengineered 3D culture arrays for on-chip production of vascularized
human mid-brain tissues and validate the propagation of α-syn pathology; and 3) Explore the cell-type specific
pathological impacts of lipid-associated polymorphic α-syn fibrils and compare the molecular structures and
interactions of these polymorphic α-syn fibrils. The expected outcomes will provide novel insights into the
molecular mechanisms underlying conformation-dependent neuropathology. Consequently, these findings will
contribute to the design and development of small molecules aimed at either inhibiting aggregations or detecting
neurotoxic aggregates. Additionally, the brain-on-a-chip established in this study has the potential to serve as a
promising drug screening platform capable of faithfully replicating cellular responses to pharmaceutical agents.
Ultimately, this study will aid in the development of advanced diagnostic and therapeutic approaches aimed at
synucleinopathies, thereby miti...

## Key facts

- **NIH application ID:** 10951926
- **Project number:** 1R21NS139178-01
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** Myungwoon Lee
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $414,191
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10951926

## Citation

> US National Institutes of Health, RePORTER application 10951926, Investigating the interplay between polymorphic α-syn fibril conformation and cell-dependent pathology (1R21NS139178-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10951926. Licensed CC0.

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