# RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $371,948

## Abstract

RNA decay is a critical component of RNA homeostasis. Transcriptionally active cells such as neurons
have developed intricate pathways for regulating RNA turnover and balancing this process with RNA synthesis.
During the initial funding period, we uncovered widespread abnormalities in RNA stability in cells from individuals
with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), implicating dysfunctional
RNA clearance pathways in disease pathogenesis. We also showed that many of these abnormalities could be
recapitulated by the deposition of TDP43, a nuclear RNA binding protein and splicing factor that is mislocalized
to the cytoplasm in >95% of ALS patients and the most common subtype of FTLD (FTLD-TDP). In probing the
downstream consequences of TDP43 deposition, we discovered that TDP43 accumulation preferentially affects
the splicing of mRNAs encoding ribosomal proteins, leading to excessive intron retention and mRNA
destabilization. Based on these results, we hypothesize that TDP43 mislocalization and accumulation in ALS
and FTLD-TDP destabilizes ribosomal protein-encoding mRNAs, compromising translation and interfering with
RNA decay mechanisms that rely on active translation, including nonsense-mediated RNA decay (NMD).
Together, these phenomena would be expected to trigger a vicious cycle culminating in RNA and protein
dyshomeostasis, and eventually neurodegeneration. The current proposal builds on data from the initial funding
period to (i) elucidate the mechanism of RNA destabilization by TDP43, (ii) categorize the impact of RNA
destabilization on protein translation and RNA homeostasis; and (iii) evaluate the therapeutic potential of two
promising genetic modifiers, UPF1 and YTHDF2, for their ability to restore RNA homeostasis and extend
neuronal survival in human neuron models of ALS and FTLD-TDP. These goals are mirrored by our long-term
objectives: to crystalize the function of TDP43 in neurons and other cell types, and harness this information to
devise effective neuroprotective strategies for ALS, FTLD-TDP and related TDP43-proteinopathies.

## Key facts

- **NIH application ID:** 10206705
- **Project number:** 2R01NS097542-06
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Sami Barmada
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $371,948
- **Award type:** 2
- **Project period:** 2016-08-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10206705

## Citation

> US National Institutes of Health, RePORTER application 10206705, RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration (2R01NS097542-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10206705. Licensed CC0.

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