The role of the serotonin 5-HT4 receptor in motor and non-motor symptoms of Parkinson’s disease

Informazioni relative al progetto

HT4PD

ID dell’accordo di sovvenzione: 894207

DOI

10.3030/894207

Progetto chiuso

Data della firma CE 20 Marzo 2020

Data di avvio 1 Gennaio 2021

Data di completamento 31 Dicembre 2023

Finanziato da

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Costo totale

€ 295 061,76

Contributo UE

€ 295 061,76

Coordinato da

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 1 - HT4PD (The role of the serotonin 5-HT4 receptor in motor and non-motor symptoms of Parkinson’s disease)

Periodo di rendicontazione: 2021-01-01 al 2023-12-31

Sintesi del contesto e degli obiettivi generali del progetto

Parkinson’s Disease (PD) is the second most common, progressive, adult onset, neurodegenerative disease in Europe and is characterized by the loss of midbrain dopaminergic neurons and the formation of Lewy bodies in the remaining dopaminergic neurons, causing motor impairment such as bradykinesia, rigidity and slow movement. Dopamine (DA) via L-Dopa therapy ameliorates many but not all symptoms and induces uncontrollable L-Dopa induced dyskinesia (LID), a complicated and debilitating side effect that affects almost all patients following 5-10 years of chronic treatment. L-Dopa induced dyskinesia (LID) affects up to 90% of patients treated with L-DOPA and currently no treatment to ameliorate symptoms exist. There is an urgent need to better understand the pathophysiology underlying this important treatment side effect and to develop drugs to reduce symptoms.

It is known that the neurotransmitters systems of Dopamine and Serotonin interact with each other and it is known that neurons producing serotonin can also metabolize and release L-DOPA which Is thought to contribute to the L-DOPA induced dyskinesia.

We study specific serotonin receptors to better understand this functional interaction and to identify targets for pharmacotherapy aiming to alleviate the dyskinesia. We want to determine the expression pattern of serotonin receptors on a cellular level, determine how modulation thereof alters responses to the drug L-DOPA and to LID in a mouse model of Parkinson.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

We are in the process of studying the role a serotonin receptor in the context of L-DOPA induced dyskinesia and have shown that modulating receptor activity also impacts on the severity of L-DOPA induced dyskinesia.
We are currently investigating the molecular underpinnings of this functional interaction in a cell–specific context.

We have shown that pharmacological activation of 5-HT4 receptor activity reduces L-DOPA induced dyskinesia in a mouse model of Parkinson's disease. We further found that this activation does not impact negatively on the anti-akinetic effect of L-DOPA.
Using the RNAscope technology and qPCR, we show that the 5-HT4 receptor in the dorsal striatum is predominantly expressed in D2-receptor expressing medium spiny neurons (MSNs) and that its expression is enhanced in response to Dopamine depletion and L-DOPA treatment.
We therefore conclude that the anti-LID action of 5-HT4R agonssim is mediated via the D2-MSNs.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

This is the final report for the grant, but we plan to further investigate the role of this receptor in LID.

RNAscope for 6-OHDA lesioned striatum