# The role of ADAR2-associated RNA editing in pathogenesis of ALS

> **NIH VA I01** · JAMES J PETERS VA  MEDICAL CENTER · 2020 · —

## Abstract

Amyotrophic Lateral Sclerosis (ALS) is a devastating and fatal neurodegenerative disease that is
characterized by progressive muscle weakness and eventual paralysis. The known risk factors for ALS are
increasing age and male sex; recent data also implicate military service, thus putting an additional burden on
the VA healthcare system. Approximately 90% of all ALS cases are classified as sporadic ALS (sALS) with no
family history of the disease. The remaining cases are inherited in a dominant fashion, and mutations in ~30
genes (most commonly in C9orf72, SOD1, TARDBP, FUS) are currently known to cause ALS.
 Hyperexcitability that stems from pathophysiological disturbance of glutamatergic transmission has
been reported in all types of ALS cases, and may be a common disease pathway that predisposes
motoneurons to degeneration. It has been suggested that the glutamatergic (Glu) deficit in ALS may result
from altered function of the AMPA Glu receptors due to inefficient RNA editing of the GluA2 AMPA subunit.
The GluA2 editing is catalyzed by the editing enzyme ADAR2. Our data, as well as data published by others,
showed the downregulation of ADAR2 and inefficient editing of the GluA2 in the motor cortex of patients with
C9orf72-associated ALS (C9 ALS) as well as in spinal motoneurons of patients with sALS. We also reported
the downregulation of ADAR2 and the consequent decrease of editing in several of its targets in animals
subjected to spinal cord injury (SCI). Moreover, in SCI these events are triggered by inflammatory response
and result in changes in gene expression that are likely to contribute to post-SCI motoneuron hyperexcitability.
 Based on these data and the fact that, as in SCI, neuroinflammation is present in ALS, we hypothesize
that: (1) ADAR2 is downregulated in both C9 ALS and sALS, leading to alterations in RNA editing in its targets.
In particular, in addition to GluA2, ADAR2 editing of other molecules which are important for neuronal
excitability [such as, GluA3-4, kainate receptor subunits GluK1-2, serotonin 2C receptor (5-HT2CR), as well as
potassium (Kv1.1) and calcium (Cav1.3) channels] is also altered in C9 ALS and sALS; (2) The downregulation
of ADAR2 in ALS results from several different pathological features associated with the disease. Whereas the
decrease of ADAR2 in sALS is triggered by neuroinflammation, the availability of the functional ADAR2 in C9
ALS is also influenced by its cytoplasmic retention, which is caused by a disruption of nucleocytoplasmic
transport.
 We will test these hypotheses by characterizing ALS-associated alterations (1) in the ADAR2
expression and localization and (2) in editing of the transcripts that are targeted by ADAR2. These studies will
be performed in laser microdissected neurons obtained from autopsy tissues of patients with C9 and sporadic
ALS (Aim1) as well as in motoneurons differentiated from human induced pluripotent stem cells (hiPSC)
derived from ALS patients (Aim2). In addition,...

## Key facts

- **NIH application ID:** 9815460
- **Project number:** 5I01BX003625-03
- **Recipient organization:** JAMES J PETERS VA  MEDICAL CENTER
- **Principal Investigator:** STELLA DRACHEVA
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-10-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815460

## Citation

> US National Institutes of Health, RePORTER application 9815460, The role of ADAR2-associated RNA editing in pathogenesis of ALS (5I01BX003625-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9815460. Licensed CC0.

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