# Adult-onset Purkinje cell loss in cerebellar dysfunction

> **NIH NIH F31** · BAYLOR COLLEGE OF MEDICINE · 2022 · $46,752

## Abstract

PROJECT SUMMARY/ABSTRACT
Neurodegeneration underlies many major neurological diseases. Cerebellar Purkinje cell degeneration is a
hallmark of ataxia, a disorder that entails poor motor coordination. However, a growing consensus argues that
conditions traditionally thought of as circuit disorders, such as tremor and dystonia, may also involve cerebellar
degeneration. This debate is due in part to technical limitations. Current human imaging techniques lack the
single-cell resolution necessary to reveal localized cell loss, and postmortem studies only inform the end-state
of disease and suffer from a scarcity of tissue samples, particularly from dystonia patients. Meanwhile, rodent
work suggests that Purkinje cell loss has diverse effects on behavior, although these studies often involve the
disruption of multiple cell types and prolonged developmental deficits, which make directly attributing behavioral
outcomes to Purkinje cell death difficult. To address these challenges, we use a genetic mouse model that
initiates Purkinje cell-specific death with temporal precision. Preliminary data suggests that adult-onset Purkinje
cell death causes progressive motor dysfunction that transitions through ataxia, tremor, and dystonia. This
proposal tests the hypothesis that Purkinje cell loss drives progressive functional changes that uniquely impact
motor behavior. Different regions of the cerebellum control distinct behaviors. Therefore, the first aim tests
whether adult-onset Purkinje cell loss causes behavioral defects depending on the region affected. A battery of
behavioral tests will track how motor dysfunction emerges, and immunohistochemistry and neural tracing will
reveal how cerebellar circuit architecture changes with degeneration and motor function deterioration. The
second aim tests how progressive Purkinje cell loss impacts the firing activity of the cerebellar nuclei, which
receive Purkinje cell input and project to other parts of the motor circuit. In vivo electrophysiological recordings
from the cerebellar nuclei of awake mice experiencing degeneration-induced motor defects will be used to
determine how Purkinje cell loss dynamically shapes neuronal dysfunction. In addition, this aim will determine
whether the beneficial effects of deep brain stimulation to the cerebellar nuclei in motor dysfunction hold true
during Purkinje cell loss. The completion of these aims will define the impact of Purkinje cell death in ataxia,
tremor, and dystonia and the mechanisms by which a single insult to a circuit can exert diverse consequences
on motor function. The fellowship training plan includes designing and performing these experiments, analyzing
the data, and writing and presenting the work in a supportive, resource-filled training environment.

## Key facts

- **NIH application ID:** 10536852
- **Project number:** 1F31NS129279-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Sarah Donofrio
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536852

## Citation

> US National Institutes of Health, RePORTER application 10536852, Adult-onset Purkinje cell loss in cerebellar dysfunction (1F31NS129279-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10536852. Licensed CC0.

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