# Deciphering the Role of the Pumilio1 in Two Distinct Neurological Diseases

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $634,219

## Abstract

This competing renewal continues the work of our first R01 (awarded in 2019) to better understand why
different mutations in the RNA-binding protein PUM1 cause two very different phenotypes. One is a mild, late-
onset ataxia, the other is a severe neurodevelopmental syndrome, although both fall under the rubric of
Spinocerebellar ataxia type 47 (SCA47). Interestingly, we were studying another SCA (SCA1) when we found
that PUM1 regulates the levels of the relevant protein, ataxin1. This was the first indication that PUM1,
previously known for its role in developing gametes, is important for neurological function in mice. PUM1 has
several mechanisms of action that it can use to regulate different targets, but in the case of ATXN1 it directly
binds to the 3'UTR to repress it. PUM1 heterozygous mice therefore develop an adult-onset ataxia very much
like SCA1, due to overproduction of ATXN1 in the cerebellum. PUM1 knockout mice are sicker, being small
from birth and born at lower Mendelian ratios. Crossing the PUM1 hets with SCA1 knockin mice exacerbates
the SCA1 phenotype, while crossing PUM1 hets with ATXN1 hets (who have no phenotype) rescues the PUM1
loss-of-function ataxia. These observations prompted us to look for human patients bearing PUM1 variants,
and we initially identified 15 individuals with either deletions or missense mutations. The most severe
mutations (deletion or R1147W, reducing PUM1 protein levels by ~50%) cause PADDAS (PUM1-associated
developmental delay and seizures); the mildest mutation (T1035S) reduces PUM1 by only 25% and causes
adult-onset PRCA (PUM1-related cerebellar ataxia). Although the phenotypic severity tracks with protein
dosage, the few PUM1 targets that were known at the time were upregulated to the same extent in cell lines
derived from PRCA and PADDAS patients. We therefore hypothesized that whereas the mild PRCA mutation
would primarily cause target dysregulation, the more severe PADDAS mutation disrupts PUM1's native
interactors in addition to their downstream targets. To test this dual hypothesis, over the past four years we
mapped PUM1 targets and interactors in the mouse brain (cortex, cerebellum, hippocampus), finding
particularly strong interactions with ubiquitin ligases, mTOR, several RNA-binding proteins (FMRP, AGO2,
CNOT1, RBFOX3), and a number of mitochondrial proteins. Our studies in patient-derived cell lines and in
vitro experiments seem to bear out our dual hypothesis, but the crucial experiment now is to study PRCA and
PADDAS mouse models (which we have in hand) in order to understand the distinct pathogenic pathways for
each disease as well as to understand how PUM1 interactions support healthy brain function. We will therefore
characterize the PRCA and PADDAS mouse models, create molecular profiles of the targets and interactors that
are altered in each model, and determine the role of mitochondrial dysfunction in the broad range of symptoms
that occur in PADDAS.

## Key facts

- **NIH application ID:** 10883271
- **Project number:** 2R01NS109858-06
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Vincenzo Alessandro Gennarino
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $634,219
- **Award type:** 2
- **Project period:** 2019-06-15 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883271

## Citation

> US National Institutes of Health, RePORTER application 10883271, Deciphering the Role of the Pumilio1 in Two Distinct Neurological Diseases (2R01NS109858-06). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10883271. Licensed CC0.

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