# Engineering therapeutic TRIM11 disaggregases for Alzheimer's Disease-Related Dementias (ADRDs)

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2022 · $446,875

## Abstract

Project Summary
Our research objective is to engineer variants of a human tripartite motif (TRIM) protein, TRIM11, with
enhanced ability to mitigate alpha-synuclein (alpha-syn) misfolding and toxicity that underlies synucleinopathies.
Synucleinopathies are common, debilitating neurodegenerative disorders that afflict millions of people
worldwide and include Parkinson's Disease, Multiple System Atrophy and Lewy Body Dementia, an
Alzheimer's Disease-Related Dementia [ADRD]). In all synucleinopathies, the proteostasis network fails to
counter the misfolding of the small presynaptic protein alpha-syn. alpha-Syn populates a range of misfolded
conformers ranging from soluble toxic oligomers to self-templating amyloid fibrils capable of initiating and
propagating disease de novo. alpha-Syn fibrils cluster into large cytoplasmic inclusions termed Lewy Bodies, a
pathological hallmark of synucleinopathies. Unfortunately, there are no effective therapeutics for
synucleinopathies. Remarkably, we have discovered that human TRIM11 can prevent and reverse the
formation of alpha-syn fibrils and reduce their toxicity in vitro and in vivo. However, we suspect that TRIM11
becomes overwhelmed and fails to counter alpha-syn misfolding in synucleinopathies. Indeed, elevating
expression of TRIM11 partially mitigates alpha-syn-mediated neurodegeneration in vivo, but neuroprotection is
incomplete and significant neurodegeneration still occurs. Thus, methods to enhance TRIM11 disaggregase
activity in the degenerating neurons of synucleinopathy patients could reverse deleterious accumulation of alpha-syn and offer a solution for synucleinopathies. We hypothesize that engineering TRIM11 with enhanced
disaggregase activity will enable more effective disassembly of toxic oligomeric and amyloid forms of alpha-syn,
which could confer therapeutic benefits in synucleinopathies. Thus, we will engineer TRIM11 with enhanced
disaggregase activity against neurotoxic alpha-syn conformers. We will then assess the ability of these enhanced
TRIM11 variants to antagonize alpha-syn aggregation and toxicity elicited by alpha-syn oligomers and fibrils in
mammalian primary neurons. To do so, we will pursue three aims: (1) Engineer enhanced TRIM11 variants to
mitigate alpha-syn aggregation and toxicity in yeast; (2) Define optimal TRIM11 variants that disassemble alpha-syn
fibrils and oligomers in vitro; and (3) Define enhanced TRIM11 variants that mitigate alpha-syn aggregation and
toxicity in primary neurons. The proposed project establishes a pipeline that begins by leveraging the power of
yeast genetics to pinpoint optimal TRIM11 disaggregases from mutant libraries and culminates with their
validation at the pure protein level and in mammalian neurons. By the end of these studies, there will be a clear
“go/no go” decision for moving enhanced TRIM11 variants into mouse synucleinopathy models and ultimately
synucleinopathy patients. Moreover, by revealing how TRIM11 disaggregase activity can ...

## Key facts

- **NIH application ID:** 10539674
- **Project number:** 1R21AG079609-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** James Shorter
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $446,875
- **Award type:** 1
- **Project period:** 2022-08-20 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10539674

## Citation

> US National Institutes of Health, RePORTER application 10539674, Engineering therapeutic TRIM11 disaggregases for Alzheimer's Disease-Related Dementias (ADRDs) (1R21AG079609-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10539674. Licensed CC0.

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