# ELAVL3 in ALS/FTD

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $417,259

## Abstract

The role of RNA binding proteins (RBPs) and disruption of RNA biology is strongly implicated in
pathogenesis of several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and
frontotemporal dementia (FTD). Their role is highlighted by the fact that the key neuropathological signature
in 97% of all ALS and 50% of FTD cases is nuclear depletion, cytoplasmic mislocalization, and aggregation
of the mainly nuclear TDP-43 protein. Other RBPs that have been implicated besides TDP-43 include FUS,
hnRNPA1, hnRNPA2B1, TAF15, EWS, and MATR3. Abnormal TDP-43 has recently emerged as a critical
player in other neurodegenerative diseases including Alzheimer’s disease (AD) and limbic-predominant
age-related TDP-43 encephalopathy (LATE). RBPs have unique low complexity domains, allowing phase
changes, aggregation and propagation, key aspects of disease pathogenesis. We have recently re-analyzed
our published transcriptome profiles generated from laser captured motor neurons from ALS nervous
systems and identified that the RBP ELAVL3 is one of the most downregulated genes in the ALS profiles.
Since this is a relatively unrecognized RBP in the field of neurodegenerations, we pursued this candidate
neuropathologically with immunofluorescence. Strikingly, we find nuclear depletion, and accumulation in
cytoplasm and axons of many motor neurons that is even more prevalent than TDP-43 abnormalities. All
neurons that have TDP-43 abnormalities also have ELAVL3 abnormalities, but many neurons with ELAVL3
abnormalities do not have TDP-43 abnormalities. Strikingly, preliminary study of ALS nervous systems from
SOD1 mutant ALS and FTLD-tau, neither of which have TDP-43 abnormalities, also seem to have ELAVL3
abnormalities. Based on these findings, we therefore believe that ELAVL3 is critically involved in these and
maybe other neurodegenerations. In this grant, we have three main aims. In Aim 1, we will determine if
ELAV3 ALS neuropathology also occurs in other neurodegenerations, including FTD, AD and LATE. In Aim
2, we will seek to characterize nuclear loss of function (LOF) in cellular model of human neuron-like cells by
genome editing the RNA binding domain and reading out a variety of candidates, cell viability and RNA-seq.
In addition, we will use eCLIP-seq to determine the RNA binding targets of ELAVL3 and the possible
downstream disruptions created by LOF. In Aim 3, we will seek to characterize cytoplasmic toxicity through
by genome editing ELAVL3’s nuclear localization signal in our cellular model and reading out a variety of
candidates, cell viability and RNA-seq. In addition, we will characterize stress granule formation and
autophagy, two highly implicated pathways in ALS. We will compare LOF and GOF using bioinformatics of
the RNA-seq and eCLIP-seq profiles and validate. By the end of these studies, we will know the significance
of this under-recognized RBP in neurodegenerations and have hypotheses with which to test in more
mechanistic stud...

## Key facts

- **NIH application ID:** 10196754
- **Project number:** 1R21NS121805-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** JOHN RAVITS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $417,259
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10196754

## Citation

> US National Institutes of Health, RePORTER application 10196754, ELAVL3 in ALS/FTD (1R21NS121805-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10196754. Licensed CC0.

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