# Design and characterization of Nanobodies to dementia-related α-synuclein strains in Parkinson’s disease

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $453,658

## Abstract

Project Summary
Parkinson's disease (PD) is the second most common neurodegenerative disorder. The typical hallmark
of PD is the abnormal accumulation of misfolded α-synuclein (α-syn) and dopaminergic neuron loss in the
substantia nigra. This results in the classic motor manifestations of PD, including tremor, bradykinesia,
rigidity, and postural instability. Braak's theory described the disease progression as prion-like α-syn
spreading, and the PD-related cognitive impairment is due to the increased burden caused by α-syn
spreading in the cortex of afflicted individuals. During the disease progression, 50-80% of PD patients
develop dementia (PDD), showing increased morbidity and mortality above those with PD alone. To study
the roles of α-syn in PD disease progression, we have amplified α-Syn from PD and PDD patients using
PMCA (protein misfolding cyclic amplification). We have determined that the amplified α-syn from PD and
PDD patients are different strains and the PDD strain α-syn exhibits more severe neurotoxicity than the
PD strain. These two distinct α-Syn strains could potentially be used as biomarkers for PD disease
progression and drug targets. However, further studies on the roles of these two α-syn strains during the
PD progression have been impeded by a lack of reagents for direct recognition of these two α-syn strains.
In response, we have designed a new library of synthetic nanobody variants that are redox stable, by
removal of the disulfide bond, and have identified a number of nanobodies that recognize α-syn preformed
fibrils (PFF), but not the monomeric form. Two out of the five nanobodies that we characterized showed
strain selectivity for the phosphorylated α-syn at serine 129 PFF over wild type PFF. The overall objective
of this proposal is to design and characterize α-syn strain-specific nanobodies that can recognize either
PD- or PDD-strain α-syn, and to test the efficacy of PFF-specific nanobodies in preventing the cell-to-cell
transmission of α-syn PFF. Accomplishing this objective will contribute to our long-term goal to understand
the roles of α-syn strains in the progression from PD to PDD, which is critical for the development of α-syn
strains as biomarkers for PD progression, and to develop new therapeutics for PD. These nanobodies
could potentially provide new therapeutic treatment for PD by preventing α-syn PFF spreading. Lastly,
nanobodies recognizing distinct strains can also be applied to study other α-synucleinopathies, including
dementia with Lewy body and multiple system atrophy.

## Key facts

- **NIH application ID:** 10194984
- **Project number:** 1R21AG072009-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Wenjing Wang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $453,658
- **Award type:** 1
- **Project period:** 2021-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10194984

## Citation

> US National Institutes of Health, RePORTER application 10194984, Design and characterization of Nanobodies to dementia-related α-synuclein strains in Parkinson’s disease (1R21AG072009-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10194984. Licensed CC0.

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