# The role of SUMOylation in Tau-mediated pathology

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $386,009

## Abstract

Our poor understanding of the molecular mechanisms that underlie the cognitive and behavioral impairments
that characterize Alzheimer’s disease stands as a critical barrier to identifying effective treatments for Alzheimer’s
disease. This project seeks to address this gap in our understanding by examining the ability of SUMOylation, a
post-translational modification during which small peptides called small ubiquitin-like modifiers (SUMOs)
covalently attach to lysine residues on target substrates, to control the pathological actions of tau – a central
component in the molecular etiology of the disease. SUMOylation is a reversible process with various effects on
protein function, including regulation of localization, stability and activity of many cellular proteins, as well as
nuclear integrity, chromosomal segregation and gene expression. There are three known SUMO paralogs in
vertebrate brains: SUMO1-3, with SUMO2 and 3 sharing ~95% sequence homology (and not functionally
differentiated) often collectively referred to as SUMO2/3. Interestingly, SUMOylation is dysregulated in the
hippocampus of Alzheimer’s Disease patients. In preliminary studies we have been able to link tau SUMOylation
to tau aggregation and toxicity with SUMO2 conjugation (but not SUMO1) protecting against tau aggregation
and toxicity. SUMO2 was also found to decrease aggregated tau release. Moreover, mimicking SUMO2 covalent
binding to tau rescued the oligomeric tau-induced impairment of long-term potentiation (LTP), a type of synaptic
plasticity thought to underlie memory formation, and memory loss in a mouse model of fronto-temporal dementia.
In this proposal, we will build on these observations by pursuing the following specific aims: 1) determine if
upregulating SUMO2 conjugation rescues tau-induced defects in synaptic function; 2) determine if upregulating
SUMO2 conjugation rescues tau-induced memory defect in mice; 3) test whether the rescuing effects of
upregulating SUMO2 conjugation depend upon modulation of tau oligomer formation. These aims will be
addressed through a combination of electrophysiological, behavioral, biophysical, and biochemical techniques
in wild-type and genetically modified mice. Upon the completion of these experiments, we will identify the
mechanisms whereby SUMOylation controls the development of tau-related impairments in Alzheimer’s disease
and in fronto-temporal dementia, and test the possibility that interventions that target SUMO2 conjugation could
constitute an effective therapeutic approach for their treatment.

## Key facts

- **NIH application ID:** 10083243
- **Project number:** 5R01NS110024-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** OTTAVIO ARANCIO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $386,009
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10083243

## Citation

> US National Institutes of Health, RePORTER application 10083243, The role of SUMOylation in Tau-mediated pathology (5R01NS110024-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10083243. Licensed CC0.

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