# Identifying kinase signaling pathways linked to tau-mediated neurodegeneration

> **NIH NIH R21** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $197,813

## Abstract

PROJECT SUMMARY
At the heart of Alzheimer’s (AD) pathogenesis, tau pathology is linked to neurodegeneration and cognitive
decline. We have spent the last decade addressing how tau exerts its toxicity in AD. Among the many tau post-
translational modifications (PTMs) that are now known to co-occur and target tau, acetylation of tau’s lysines,
which have emerged from recent cryo-EM and mass spectrometry studies, is a particularly relevant and
attractive target. Coupled with the fact that acetylation accelerates tau aggregation, prevents normal
microtubule binding, and induces prominent AD-like deficits including synaptic dysfunction and cognitive
decline, these properties would appear to set this particular PTM apart from many of the other tau PTMs that
are known to regulate tau. While acetylated tau is common to virtually all sporadic AD brains, there remain few
reliable models to unravel the signaling events and enzymes that converge on this idea. In our view, this gap
needs to be overcome if we hope to unravel mechanisms that drive tau pathogenesis. We identified a new
signaling pathway in which the Parkinson’s disease (PD)-relevant kinase LRRK2 acts upstream to regulate
HDACs and therefore indirectly controls tau acetylation. We hypothesize that LRRK2 and other related “HDAC
kinases” act as master regulators of HDAC function, with their end goal of preventing the accumulation of
acetylated tau and thereby protecting against tau toxicity. In Aim-1, we develop a new model based on an
engineered cytoplasmic CBP acetyltransferase to precisely target cytoplasmic tau and then assess the extent
of tau pathology, synaptic dysfunction, tau seeding, and tau propagation. Having narrowed in on HDACs 3/6 as
the only tau-associated HDACs among all human HDACs, we will deliver them to neurons and determine
whether synergism among HDACs converges onto tau to suppress its toxicity. In Aim-2, we focus on the
upstream kinases that coordinate HDAC activity. We explore LRRK2 as a very attractive hit identified in a mini
screen that modulates HDAC3/6 function. We will manipulate LRRK2 function in mouse neurons, mice, and
human iPSC neurons to evaluate downstream consequences on HDACs and tau. Our proposal will shed light,
not only on AD-relevant HDACs, but also open up new therapeutic avenues (e.g., the targeting of upstream
kinases) to suppress toxic tau species in the brain. This proposal is therefore both innovative and significant
since upstream HDAC regulatory kinases including LRRK2 and PKC hold promise as unanticipated regulators
of HDAC activity. This will expand our repertoire of targetable pathways in tauopathies that include AD and
even PD as well.

## Key facts

- **NIH application ID:** 10909358
- **Project number:** 5R21AG084216-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Todd Jonathan Cohen
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $197,813
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909358

## Citation

> US National Institutes of Health, RePORTER application 10909358, Identifying kinase signaling pathways linked to tau-mediated neurodegeneration (5R21AG084216-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10909358. Licensed CC0.

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