Modeling Impulse Control Disorders in Parkinson's Disease and Biomarker Validation: Translational Approaches – DOPAMINE

Impulse control disorders (ICD) are the main neuropsychiatric side effect induced by pharmacological treatments in Parkinson's disease. They are characterized by behavioral addictions which affect around a quarter of patients and represent a major clinical and public health problem due to the lack of therapeutic options. These behavioral addictions manifest in the form of eating disorders ("binge eating") or hypersexuality.
This project aims to improve the monitoring and management of ICD by combining experimental models and clinical research, in order to identify specific molecular signatures of these behavioral disorders and their severity. At the preclinical level, this will be done with the modeling of impulse control disorders (hypersexuality and eating behavior disorder) in a progressive experimental model of Parkinson's disease in rats by targeted overexpression of alpha-synuclein in the substantia nigra, followed by chronic treatment with a D2/D3 dopaminergic agonist inducing ICD in patients (pramipexole). In parallel with this experimental aspect, a longitudinal clinical study will be carried out in parkinsonian patients suffering from hypersexuality or eating disorders in comparison with a group of patients free from ICD. Blood samples taken at regular intervals will make it possible to set up biobanks which will be used to screen for molecular markers of interest. We will focus on microRNAs which are small non-coding RNAs having the capacity to downregulate the transcription of several target genes. They are present in the brain and in biological fluids (blood) and their dysregulation has been shown in several neurodegenerative or psychiatric diseases. Following these longitudinal studies, the creation of both preclinical and clinical biobanks will allow the cross validation of microRNAs as blood biomarkers by high throughput screening. These specific biomarkers will subsequently make it possible to improve the management of these side effects of antiparkinsonian treatments by allowing early identification of patients at risk. They will also be used as surrogate markers for monitoring the severity of ICD in clinical practice and during therapeutic trials. In addition, the identification of these microRNAs and of their transcriptional targets will improve our understanding of the pathophysiology of ICD and promote the development of innovative therapeutic strategies by identifying new molecular targets for these extremely deleterious side effects of antiparkinsonian drugs.