# Alpha-synuclein Regulates Dopamine Transporter Functions

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $417,037

## Abstract

Altered dopamine (DA) transporter (DAT) activity is implicated in Parkinson disease. Missense
DAT mutations are directly associated with adult early-onset Parkinsonism and progressive
dopaminergic neurodegeneration. Increased α-synuclein, a protein partner of DAT, is also
implicated in Parkinson disease and other neurodegenerative diseases. Over 80% of patients
with longstanding Parkinson disease will develop dementia. Multiplication of α-synuclein gene in
human is involved in the development of PD and/or dementia with Lewy bodies. The long-term
goal of this study is to determine how DAT dysfunction following α-synuclein overexpression
disrupts neuronal and network function, prior to cell loss. Our primary objective is to determine
the underlying mechanism/s of the progression of pathology and identification of therapeutic
targets. Determining the etiology of DA signaling dysfunction in Parkinson disease and other
neurological disorders have been challenging as DAT regulates the spatiotemporal
characteristics of DA transmission by regulating: 1) uptake of released DA, 2) spontaneous
firing activity of DA neurons and 3) non-vesicular DA release (efflux). Therefore, it is critical to
first dissect the pathological regulations of these functions at a single neuron, then determine
the interrelated functional changes in the diseased state. Our preliminary and published data
suggest there is a bidirectional interaction between DAT and α-synuclein, where the mere
existence of DAT at the neuronal membrane recruits α-synuclein to the membrane. We found
membrane recruited α-synuclein directly interacts with DAT, alters the ionic coupling of DAT by
increasing an inward depolarizing Na+ current, inhibits the DAT mediated DA uptake, increases
the magnitude and duration of Ca2+ spikes in DA neurons and causes a 7-fold increase in DA
efflux resulting in diminished DA recycling. These effectively challenge the regulation of synaptic
DA levels in the short-term and neuronal integrity in the long-term. Our pilot data suggest this
problem quickly scales up to the level of cellular activity and network function. Collectively,
these data support the overarching hypothesis that increased α-synuclein in DA neurons
increases firing activity of DA neurons and DA efflux via a DAT and Ca2+-dependent mechanism
leading to disruption of DA transmission and neuronal communication. To address this
hypothesis, we will use molecular, pharmacological and electrophysiological approaches with
particular emphasis on neurochemical and molecular mechanisms of dopamine
neurotransmission.

## Key facts

- **NIH application ID:** 9995584
- **Project number:** 5R01NS071122-09
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Habibeh Khoshbouei
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $417,037
- **Award type:** 5
- **Project period:** 2010-09-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9995584

## Citation

> US National Institutes of Health, RePORTER application 9995584, Alpha-synuclein Regulates Dopamine Transporter Functions (5R01NS071122-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9995584. Licensed CC0.

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