# Molecular Mechanisms of Purkinje Cell Degeneration in Ataxia-Telangiectasia

> **NIH NIH R21** · ROCKEFELLER UNIVERSITY · 2021 · $466,125

## Abstract

PROJECT SUMMARY
 Ataxia-telangiectasia (A-T) is an autosomal recessive, multi-system, disorder caused by mutations in the
universally expressed ataxia-telangiectasia, mutated (ATM) gene affecting approximately 1:40,000-1:100,000
births, for which there is no cure. Characterized by progressive cerebellar neurodegeneration, there are no
effective treatments for A-T, with patients succumbing to chronic sinopulmonary infections or A-T related cancer
by the third decade of life. Furthermore, the cause of cerebellar neurodegeneration, chiefly affecting Purkinje
cells (PCs), the primary output neuron of the cerebellum, has remained elusive since the first descriptions of A-
T nearly 80 years ago, largely because mouse models do not recapitulate the human cerebellar phenotype of
PC death. Thus, the critical objectives of this proposal are to develop the first human A-T model system that
recapitulates the cerebellar phenotype and to use that system to identify molecular differences between patient
and unaffected PCs as well as differences between human and mouse PCs. Toward that end, we will use our
recently published protocol (Buchholz et al, 2020) to generate an induced pluripotent stem cell (iPSC) model
system and use that system to study the effects of A-T patient mutations on developing human PCs.
 Using our protocol, we have been able to differentiate cerebellar Purkinje cells that match young adult
PCs on a transcriptomic level (Buchholz et al., 2020) and fire specific calcium currents in co-culture with their
target neurons, granule cells (GCs). Our specific aims in this proposal are therefore to use this protocol to
differentiate iPSCs derived from patients with A-T, as well as unaffected control iPSCs derived from family
members, into PCs to study A-T PC phenotypes, including defects in survival and synaptic function in co-culture
with GCs. To discover molecular changes in Purkinje cells with the A-T mutation, we will study global gene
expression and protein phosphorylation compared to controls. Critically, we will then use CRISPR-Cas9 prime
editing to correct the ATM mutation and test for rescue, including identifying key changes in rescued versus
mutant gene expression and proteomics. Taken together, these studies will identify pathways involved in A-T
PC phenotypes and will discover altered pathways that could provide novel targets for therapy.

## Key facts

- **NIH application ID:** 10193587
- **Project number:** 1R21NS121438-01
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Mary Elizabeth Hatten
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $466,125
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10193587

## Citation

> US National Institutes of Health, RePORTER application 10193587, Molecular Mechanisms of Purkinje Cell Degeneration in Ataxia-Telangiectasia (1R21NS121438-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10193587. Licensed CC0.

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