# Role of Transglutaminase 2 in Synucleinopathies

> **NIH NIH R21** · RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL · 2021 · $431,750

## Abstract

Project Summary:
α-Synuclein is a key pathogenic protein in Parkinson’s disease (PD) and Dementia with Lewy
Bodies (DLB) based on genetic, neuropathologic, cell biologic and animal model studies. This
intrinsically disordered protein can oligomerize, misfold, and form fibrils that propagate across
neurons in the brain and accumulate in Lewy bodies and Lewy neurites. It is believed that the
oligomeric forms of α-synuclein represent the toxic species, and these can nucleate monomers
to perpetuate the pathologic process underlying the progressive nature of the disease. Thus,
understanding the factors that trigger the initial steps of oligomerization is critical for designing
disease modifying therapeutic strategies. A hitherto under-explored factor is molecular cross-
linking of α-synuclein by transglutaminase 2 (TG2) between glutamine and lysine residues
creating intermolecular isopeptide bonds that are highly resistant to proteolysis. Several lines of
evidence indicate that TG2 cross-links α-synuclein leading to its aggregation in vitro, in cultured
mammalian cells, in yeast cells, and in the brains of transgenic mice. We have found that the
phenotype of α-synuclein transgenic mice is exacerbated by over-expressing TG2 and is
mitigated by knocking it out. Studies in patients with α-synucleinopathy also corroborate the
hypothesis that TG2 plays a pathogenetic role. TG2 expression is increased in the substantia
nigra and cerebrospinal fluid of PD patients compared with control subjects, TG2 co-localizes with
α-synuclein aggregates in stressed dopaminergic neurons in PD brains, and TG2-catalyzed
cross-links co-localize with α-synuclein in Lewy bodies in PD and DLB affected brains. Despite
this body of evidence, it remains unknown whether TG2-mediated cross-linking of α-synuclein
promotes the propagation of these aggregates across the brain. We hypothesize that it does and
propose to test this hypothesis through two specific aims: 1) Investigate if the presence of TG2
and its expression level influence the propagation of α-synuclein fibrils, and 2) Examine if the
transglutaminase enzymatic activity of TG2 is responsible for this process. Knowledge gained
from these studies will address a fundamental scientific question about the pathogenetic
mechanism of TG2-mediated α-synuclein propagation and aid in developing targeted disease
modifying therapeutic for synucleinopathies.

## Key facts

- **NIH application ID:** 10285001
- **Project number:** 1R21NS123770-01
- **Recipient organization:** RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
- **Principal Investigator:** M. Maral Mouradian
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $431,750
- **Award type:** 1
- **Project period:** 2021-07-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10285001

## Citation

> US National Institutes of Health, RePORTER application 10285001, Role of Transglutaminase 2 in Synucleinopathies (1R21NS123770-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10285001. Licensed CC0.

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