# Transcriptomic Approaches to TDP-43 Pathology

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $234,811

## Abstract

TDP-43 pathological inclusions are associated with a spectrum of clinical syndromes including behavioral
variant frontotemporal degeneration (bvFTD), primary progressive aphasia (PPA), or amyotrophic lateral
sclerosis (ALS). Moreover, approximately 10% of bvFTD or PPA patients share neuromuscular features of ALS
(ALS-FTD). Beyond the clinical complexities of the FTD and ALS spectrum associated with TDP-43, there are
also many shared genetic links between these conditions including C9orf72 repeat expansions and TARDBP
mutations that can result in bvFTD and/or ALS as well as disparate genetic mutations that exclusively result in
FTD (e.g., GRN) or ALS (e.g., SOD1). The overall hypothesis of this project is that molecular heterogeneity,
and specifically regionally-variable gene expression, contributes to macroscale network vulnerability
contributing to a spectrum of clinically heterogeneous syndromes. It is critical to better understand the
neuroanatomic and clinical features of gene expression in the current era of precision medicine in which there
are antisense oligonucleotide (ASO) and adeno-associated vector (AAV) viral genetic therapies that aim to
modify gene expression which have recently received FDA-approval for neuromuscular disorders and are
underway for C9orf72 and GRN. While prior studies suggest that genetic and epigenetic variation contributes
to the spectrum of heterogeneity in FTD and ALS, evaluations of the relationships between gene expression
and disease phenotype are rare. This project aims to establish biological and genetic factors that influence
regional anatomic disease burden which will provide regionally-specific biomarkers to track in emerging genetic
therapies. We propose three Specific Aims: (1) Identify regional relationships between molecular gene
expression and macroscale networks that bias risk for a specific clinical syndrome. We will interrogate publicly-
available regional RNA microarray data and relate patterns of covariance from TDP-associated genes to
structurally and functionally-derived networks that are associated with distinct bvFTD, PPA, and ALS
syndromes; (2) Establish convergence between gene expression and in vivo neuroimaging networks of FTD
and ALS patients. We will relate regional RNA microarray data of healthy individuals to in vivo cortical
thickness and graph-theoretic network features (e.g., degree, path length) defined in Core E that are derived
from FTD and/or ALS patients with inherited disease recruited from Core B and scanned using 3T MRI in Core
C. We hypothesize that the regional distribution of gene covariance in typical adults will relate to the regional
distribution of neurodegeneration in individuals with genetic mutations; and (3) Determine the manner in which
modifiers of gene expression impact network structure in FTD & ALS. Using principles of network control
theory we will leverage naturally-occurring heterogeneity in gene expression, including epigenetic (e.g., DNA
methylation) ...

## Key facts

- **NIH application ID:** 9937388
- **Project number:** 1P01AG066597-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Corey T McMillan
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $234,811
- **Award type:** 1
- **Project period:** 2020-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937388

## Citation

> US National Institutes of Health, RePORTER application 9937388, Transcriptomic Approaches to TDP-43 Pathology (1P01AG066597-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9937388. Licensed CC0.

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