# Alpha-synuclein driven cellular changes and vocal dysfunction in Parkinson's Disease

> **NIH NIH R21** · UNIVERSITY OF ARIZONA · 2021 · $415,482

## Abstract

SUMMARY
Diagnosis of Parkinson’s Disease (PD) is made late, delaying treatment and limiting the ability to halt disease
progression. Treatments that target the prodromal phase of PD, prior to the appearance of the cardinal motor
signs (tremor, rigidity, etc) and the degeneration of dopamine-producing neurons, do not exist because we lack
reliable biomarkers of early disease. Based on accumulating evidence, vocal dysfunction is present during the
prodromal phase of PD and offers a convenient entry point to identify early neuropathological changes as
potential treatment targets. Data from our laboratory and others has shown that the overexpression of a known
human-PD causing gene, alpha-synuclein (α-syn, SNCA) in the rodent and finch brain, leads to early vocal
abnormalities consistent with human disease. As a synaptic protein, α-syn is critically involved in cell functions
including facilitating neurotransmitter release. Its cellular toxicity in PD has been targeted in human clinical trials
but late in the disease, when the neuropathology is already widespread. In fact, little is known about how the
physiological role of α-syn shifts to a pathophysiological one early on in PD. This R21 proposal addresses these
shortcomings by investigating early stage abnormalities in vocal motor output that can occur years before
traditional motor symptoms. We propose to develop an integrated, early stage platform for the evaluation of the
α-syn-mediated changes in neuronal and synaptic activity that drive abnormal vocal output. To do so, we use
the zebra finch model system because it has specialized song-dedicated brain nuclei that can be experimentally
targeted; cell-specific changes in activity are then directly related to the vocal output. Area X is a song-dedicated
nucleus within the finch basal ganglia. Within Area X, striatal Medium Spiny Neurons (MSNs) and Globus
Pallidus-like (PAL) projection neurons show singing-related firing activity that is directly related to variations in
song structure. When α-syn is virally overexpressed in Area X, we detect PD-like changes in song including
reduced pitch, amplitude, and abnormal timing. In Aim 1, we test the hypothesis that these song changes result
from reduced MSN activity and increased PAL activity in freely behaving birds implanted with extracellular
electrode arrays. Aim 2 tests the hypothesis that α-syn overexpression in Area X results in a time-dependent
suppression of glutamatergic currents in MSNs and enhanced GABAergic currents in PAL neurons in living brain
slices. Our powerful integrative approach uses in vivo and ex vivo measurements of neural activity to evaluate
how α-syn driven changes in specific neuronal sub-types correlates to the behavioral output. The
characterization of neuropathophysiological mechanisms underlying early stage PD-like vocal deficits will offer
new disease-modifying treatment targets.

## Key facts

- **NIH application ID:** 10283440
- **Project number:** 1R21NS123512-01
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Julie Elizabeth Miller
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $415,482
- **Award type:** 1
- **Project period:** 2021-07-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10283440

## Citation

> US National Institutes of Health, RePORTER application 10283440, Alpha-synuclein driven cellular changes and vocal dysfunction in Parkinson's Disease (1R21NS123512-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10283440. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*