# Investigating the role of TDP-43 mislocalization, structure, and post-translational modifications in the neuropathologically heterogeneous TDP-43 proteinopathies

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $1,029,657

## Abstract

PROJECT SUMMARY/ABSTRACT
 The abnormal aggregation of transactive response DNA-binding protein of 43 kDa (TDP-43) in neuronal
inclusions is the defining pathologic hallmark of approximately half of frontotemporal lobar degeneration cases
(FTLD-TDP). Substantial heterogeneity exists in the clinical disorders associated with FTLD-TDP, which
reflects regional differences in neurodegeneration. Neuropathologic studies have suggested that the regional
cortical burden of aggregated TDP-43 may be responsible for neurodegeneration and ensuing clinical
heterogeneity. However, the molecular mechanisms underlying the region-specific accumulation of aggregated
TDP-43 are not understood. We hypothesize that: 1) in view of the subdivision of FTLD-TDP Types (A-D) and
variability in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC),
presence of atypical neuropathologic features may signal novel TDP-43 structures and post-translational
modifications (PTMs); 2) among TDP-43 proteinopathies, each neuropathologic phenotype is related to a
distinct structure of TDP-43 filaments, TDP-43 PTMs, and seeding properties. To investigate these
hypotheses, we propose to combine our collective expertise in neuropathology, molecular genetics, molecular
characterization of misfolded proteins, fluorescent multiplex immunohistochemistry, digital spatial profiling,
quantitative digital image analysis, and cryo-electron microscopy to study our study population, which includes
clinicopathologically well-characterized cases from the Dementia Laboratory’s Brain Library and cases from
other researchers. The project specific aims provide a foundation for in-depth analysis of TDP-43
proteinopathies. Aim 1 combines innovative neuropathologic methods for mapping TDP-43 inclusions,
misfolded TDP-43 in different neuronal and glial populations, glial response, and for determining how TDP-43
amyloid folds relate to the phenotype. Aim 2 leverages cutting-edge technology to identify novel PTMs that
coexist with the presence of misfolded TDP-43. RT-QuIC assay might reveal differences of TDP-43 seeding
properties. Aim 3 uses the most advanced cryo-EM technology to determine the structures of the TDP-43
amyloid filaments.

## Key facts

- **NIH application ID:** 10885452
- **Project number:** 1R01NS137469-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Laura Cracco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,029,657
- **Award type:** 1
- **Project period:** 2024-04-16 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885452

## Citation

> US National Institutes of Health, RePORTER application 10885452, Investigating the role of TDP-43 mislocalization, structure, and post-translational modifications in the neuropathologically heterogeneous TDP-43 proteinopathies (1R01NS137469-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10885452. Licensed CC0.

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