# Deciphering the role of Pumilio1 in two new neurological diseases

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $21,739

## Abstract

Project Summary from R01NS109858 Parent Award
Little is known about the role of RNA-binding proteins in brain development or disease, but accumulating
evidence indicates their involvement in neurological disorders. In fact, we found that the RNA-binding protein
Pum1 is crucial for neurological function in both mice and humans. Pum1-haploinsufficient mice develop
ataxia at 5 weeks of age and show Purkinje cell degeneration at 10 weeks. Pum1 knockout mice are more sick:
they are born at a lower mendelian ratio, are smaller than wild-type, have early seizures, and more severe
cerebellar degeneration1. We then found that mutations in human PUM1 also cause two very different diseases
that parallel what we observed in mice: a mild, adult-onset pure cerebellar ataxia in patients with a mutation
that reduces PUM1 levels by ~25%, and an early-onset disorder that causes several cognitive and physical
delays, smaller size, motor incoordination, and seizures in patients with PUM1 mutations that reduce its levels
~40-60%2. But how do the specific mutations alter PUM1 function, aside from making it less stable? The most
obvious place to look is at PUM1 targets. The only published neuronal targets are ATXN1 and E2F3, and their
abundance is increased by similar amounts (~50%) in both the adult-onset ataxia and early-onset cases. The
ataxia might be explained by elevated abundance of cerebellar ATXN1, but the broader phenotype of the
developmental disorder must involve dysregulation of other PUM1 targets. There is, however, more of a puzzle
here than is first apparent. The mildest mutation, T1035S, which reduces PUM1 levels by only 25%, is in
homology domain (HD) 6; of the mutations that produce the severe, early onset phenotype, R1139W is in HD8,
and R1147W is just outside this domain. Why, then, do R1139W and R1147W produce equally severe
phenotypes, when only the former abolishes PUM1’s repressor activity? And why is T1035S so mild, when it
also abolishes PUM1’s repressor activity? We propose that the milder disease results from target
dysregulation, whereas more severe disease results when levels of PUM1 fall below a certain point (perhaps
30-40%), because its interacting partners either cannot form their normal complexes or the complexes fall
apart quickly, causing loss of function of those interactors (and loss or gain of function of downstream
targets). To test this two-part hypothesis, we will: 1) map the Pum1 targetome in the mouse brain as well as
that of Pum2, its homolog (there may be regulatory overlap between the two proteins); 2) identify PUM1
protein interactors, and 3) study the cross-talk between Pum1 and Pum2 in mice. In sum, our recent
discoveries not only define two new neurological diseases, they demonstrate that understanding the post-
transcriptional regulation of disease-related proteins, like the PUF family, can lead to the identification of new
candidate disease genes.

## Key facts

- **NIH application ID:** 10249566
- **Project number:** 3R01NS109858-02S1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Vincenzo Alessandro Gennarino
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $21,739
- **Award type:** 3
- **Project period:** 2020-09-30 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249566

## Citation

> US National Institutes of Health, RePORTER application 10249566, Deciphering the role of Pumilio1 in two new neurological diseases (3R01NS109858-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10249566. Licensed CC0.

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