# Deep Pathological Phenotyping in Frontotemporal Dementia and Motor Neuron Disease.

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $908,406

## Abstract

Abstract
This project seeks to perform deep pathological phenotyping of frontotemporal dementia (FTD) and motor
neuron disease (MND). The rationale for the proposal is that, despite the exploding basic biology of FTD
and MND, limited information is available about the strongest biological predictors of neurodegeneration
in the brains of patients. Even less is known about mechanisms underlying the striking selective
vulnerability seen in FTD and MND or what drives the clinico-anatomical overlap of the two disorders.
We will pursue these questions with a focus on TAR DNA-binding of 43 kDA (TDP-43) pathobiology, its
relationship to other emerging FTD/MND mechanisms, and its targeting of specific neuronal subtypes
within the FTD- and MND-related systems. We will further evaluate the complex neuropathological profile
seen in C9ORF72 expansion-related FTD/MND and build datasets equipped to help determine which
among the many pathological features in sporadic and C9-FTD/MND represent the strongest predictors
of neurodegeneration. Our approach seeks to overcome existing methodological barriers by combining
advanced histology, a novel tissue multiplexing platform that allows dozens of protein or RNA markers to
be quantified in situ, and single nucleus transcriptomics. We will study patients across the FTD/MND-
TDP-43 spectrum, including those with the C9ORF72 expansion, and control subjects. We aim to: (1)
Relate TDP-43 pathobiology to nuclear transport defects, cryptic exon incorporation, and DNA damage,
(2) Determine the pathological changes most prevalent in vulnerable neurons and regions and most
strongly linked to neurodegeneration, and (3) Identify transcriptional signatures of neuronal vulnerability
and TDP-43 pathobiology in FTD/MND. Successful completion of the proposed aims would resolve key
questions about the human relevance of candidate pathogenic mechanisms in FTD/MND-TDP, enabling
more informed prioritization of potential targets for human therapeutic development. The integrated
multidimensional data produced would create a deep library for testing new hypotheses as they emerge
and for generating new hypotheses. Finally, accomplishing our goals would advance a transformative
new histopathological approach to studying neurodegenerative and other complex human diseases.

## Key facts

- **NIH application ID:** 9934277
- **Project number:** 5R01NS104437-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** WILLIAM W SEELEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $908,406
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934277

## Citation

> US National Institutes of Health, RePORTER application 9934277, Deep Pathological Phenotyping in Frontotemporal Dementia and Motor Neuron Disease. (5R01NS104437-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9934277. Licensed CC0.

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