# Mechanisms of tau misfolding in neurons elucidated by deep mutational scanning and CRISPR screening

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $68,562

## Abstract

PROJECT SUMMARY/ABSTRACT
 Protein aggregation is a hallmark of neurodegenerative diseases, including Alzheimer’s, and these
diseases lack effective therapeutics. Moreover, we lack an understanding of the molecular and cellular
mechanisms controlling protein aggregation in the human brain, which would enable new therapeutic
strategies.
 The protein tau is the major constituent of aggregates in the brain in a number of neurodegenerative
diseases, collectively called tauopathies, including Alzheimer’s Disease. Although a number of disease-
associated tau mutations are known, we lack a comprehensive understanding of how sequence controls
tau aggregation and misfolding. Furthermore, tau, despite being widely expressed in the brain, aggregates
at disease-onset in only specific neuronal subtypes. This phenomenon, called selective vulnerability,
suggests that differential expression of cellular factors plays a key role in tau misfolding and
aggregation. I hypothesize that cellular factors and sequence changes control specific tau states that
determine its aggregation and misfolding in human neurons.
 Here, I propose two systematic, unbiased strategies, CRISPR-based functional genomics and Deep
Mutational Scanning (DMS), to comprehensively dissect how both sequence determinants and cellular factors
control tau misfolding and aggregation in iPSC-derived neurons. Integration of results from these studies with
biophysical and structural follow-up experiments will determine specific tau states that are essential for its
aggregation. By performing systematic studies in human neurons, I am uniquely positioned to
determine classes of tau mutations and cellular factors that underlie tau aggregation and misfolding.
 I have performed a focused proof-of-principle functional genomics screen and identified the peptidyl-
proline isomerases (PPIases) FKBP1A and PPIH as regulators of tau oligomerization. In Aim 1, I will
characterize how the PPIases FKBP1A and PPIH control tau misfolding and aggregation in collaboration with
my co-sponsor Dr. Bill DeGrado and collaborator Dr. Lukasz Joachimiak. Aim 2 uses a functional genomics
approach to identify cellular factors that control tau aggregation and misfolding. Follow-up studies will
determine how identified factors control tau conformations on-pathway to aggregation. Aim 3 uses DMS to
comprehensively determine the sequence factors that control tau aggregation and misfolding, with a specific
emphasis on dissecting the role of PTMs. Completion of these aims will result in a comprehensive
understanding of the underlying cellular factors and sequence determinants that control tau misfolding and
aggregation, and reveal potential therapeutic targets.

## Key facts

- **NIH application ID:** 10173609
- **Project number:** 5F32AG063487-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Avi Jacob Samelson
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $68,562
- **Award type:** 5
- **Project period:** 2019-06-17 → 2022-06-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10173609

## Citation

> US National Institutes of Health, RePORTER application 10173609, Mechanisms of tau misfolding in neurons elucidated by deep mutational scanning and CRISPR screening (5F32AG063487-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10173609. Licensed CC0.

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