# Deconstructing and challenging TDP-43 proteinopathies: from FTLD/ALS to Alzheimer's disease

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2021 · $381,250

## Abstract

TDP-43 pathology was first identified in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar
degeneration (FTLD), but was later found in other incurable neurological disorders including Alzheimer's
disease (AD). It is characterized by decreased solubility, hyper-phosphorylation and abnormal accumulation of
TDP-43 in the cytosolic compartment, which results in its nuclear depletion. Despite considerable effort to
investigate the function of TDP-43, we still have a very poor understanding of the molecular events underlying
TDP-43 pathogenesis. For instance, little is known about the molecular targets and mechanisms mediating its
pathological cascade, and which and how many pathways orchestrate the disease. Additionally, recent studies
indicate that TDP-43 may also play a role in AD pathogenesis by regulating Aβ42 plaque formation and tau
aggregation. A key challenge, therefore, is to identify critical proteins and pathways capable of blocking TDP-
43 toxicity and its potential interactions with concurrent Aβ42 and tau pathologies. To address this, we recently
performed an unbiased loss-of-function screen searching for modifiers of mutant TDP-43 toxicity in the
Drosophila eye. To do so, we used a next generation collection of 6,261 RNA lines against human homologues
and found 375 modifiers, including more than 100 suppressors. Our hypothesis is that a comprehensive
functional analysis of these modifiers, including therapeutic challenges in other neurodegenerative models, will
help to deconstruct and identify the most relevant pathological cascades. Therefore, this application aims at
validating, classifying and prioritizing the best TDP-43 suppressors among this constellation of modifiers (Aim
1). Additionally, we will define the therapeutic potential of the top candidates and their combinations in
additional models of FTLD, ALS and AD (Aim 2). Since co-manipulation of TDP-43, Aβ42 and tau in vivo is
very difficult to study due to the aggressive synergistic toxicity between these factors, we developed a new
optogenetic expression system to bypass this limitation. This new system allows unprecedented
spatiotemporal control of gene expression in response to light quantity, duration and direction and, thus, we will
use it to substantially increase knowledge of how these proteins interact using in vivo and ex vivo paradigms
(Aim 3). Taken together, these experiments are highly significant because they will tease apart the complex
mechanisms mediating TDP-43 proteinopathies and will provide valuable information for the development of
new therapeutic strategies. In addition, we will provide new optogenetic tools for the simultaneous analysis of
multiple neurotoxic proteins with unprecedented resolution.

## Key facts

- **NIH application ID:** 10180834
- **Project number:** 5R01AG059871-04
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Diego E Rincon-Limas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10180834

## Citation

> US National Institutes of Health, RePORTER application 10180834, Deconstructing and challenging TDP-43 proteinopathies: from FTLD/ALS to Alzheimer's disease (5R01AG059871-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10180834. Licensed CC0.

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