# Influence of Aging on Pathogenic Alpha-Synuclein Strains and Transmission Mechanism

> **NIH NIH K01** · JOHNS HOPKINS UNIVERSITY · 2020 · $130,140

## Abstract

“Influence of Aging on Pathogenic α-Synuclein Strains and Transmission Mechanism” Project Summary:
Besides α-synuclein transmission mechanism, the role of distinct strains of α-synuclein is compelling to be
understood. Understanding the influence of aging on the pathogenesis of synucleinopathies, including
Parkinson's disease (PD), PD with dementia (PDD), dementia with Lewy body (DLB) and multiple system
atrophy (MSA), is crucial for developing more effective symptomatic therapies. In this K01 proposal, three
specific aims are proposed for understanding the influence of aging: (1) To generate and characterize
pathogenic strain-specific α-syn from brain tissue/CSF of patients with PD/PDD/DLB/MSA to controls by the
factor of aging longitudinally and cross-sectionally. (2) To understand the influence of age on distinct
pathogenic α-syn strains from PD/PDD/DLB/MSA in vitro and in vivo. (3) To uncover the transmission
mechanism of age-related distinct pathogenic α-synuclein. To achieve the 3 specific aims, 6 methods/steps
are required: (i) Dr. Juan Troncoso and Dr. Liana Rosenthal will provide the training to candidate on handling
human brain tissue/CSF. Drs. Ted and Valina Dawson, and Dr. Mark Mattson will train the candidate using the
misfolded α-synuclein in brain tissue/cerebrospinal fluid (CSF) as templates, and with protein misfolding cyclic
amplification (PMCA) technique, to generate distinct α-synuclein strains. (ii) Scanning tunneling microscopy
(STM) will be applied for imaging molecular structures of distinct α-synuclein strains and distinguish the
differences, and the alternative training will be available from Dr. Chen Wang if the potential problems appear.
(iii) Atomic force microscopy (AFM) will be applied for observing assembly morphologies of distinct α-synuclein
strains. Dr. Mingdong Dong will provide the training on studying nano-mechanical properties and dynamic
growth features of distinct α-synuclein strains. (iv) Electrophysiology study on firing experiment will be hands-
on training from Dr. Antonello Bonci. This training study is to understand the intrinsic and synaptic properties
affected by distinct α-synuclein strains. (v) In vivo microscopy will be hands-on training from Dr. Da-Ting Lin.
This training includes performing all necessary surgical procedure to insert gradient index (GRIN) lens into
substantia nigra and two-photon microscopy. This study will allow candidate to study the dopamine neuronal
circuit dysfunction affected by stereotaxically injected with distinct α-synuclein strains in striatum region for
evaluation the transmission. (vi) Lymphocyte-activation gene 3 (LAG3) has been identified as α-synuclein
preformed fibrils (PFF) receptor, so it is worth to explore whether LAG3 can mediate the transmission of
distinct α-synuclein strains. Above all, this project proposed is to develop an independent research laboratory
equipped to understand the distinct strains of amyloid proteins on misfolded structures, the trans...

## Key facts

- **NIH application ID:** 9981563
- **Project number:** 5K01AG056841-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Xiaobo Mao
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $130,140
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981563

## Citation

> US National Institutes of Health, RePORTER application 9981563, Influence of Aging on Pathogenic Alpha-Synuclein Strains and Transmission Mechanism (5K01AG056841-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9981563. Licensed CC0.

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