Investigator:
Francesca Magrinelli, MD, PhD
Name of Institution:
University College London Institute of Neurology
Project Title:
Dissecting PSMF1 as a new gene for early-onset Parkinson’s disease/parkinsonism
Investigator Bio:
Dr Francesca Magrinelli is a Neurologist and Postdoctoral Researcher at the UCL Queen Square Institute of Neurology, University College London (UCL), London, UK. After completing neurology training at the University of Verona, Italy, she pursued a PhD in Neurosciences focused on the genetics of movement disorders and neurodegenerative diseases, particularly early-onset Parkinson’s disease (PD), dystonia and non-Huntington disease chorea. She spent three years of her PhD at the UCL Queen Square Institute of Neurology, where she specialized in the diagnosis and treatment of movement disorders under the supervision of Prof. Kailash Bhatia and acquired cutting-edge, dry and wet lab skills in Prof. Houlden’s neurogenetics research lab. After being awarded her PhD in 2021, she was granted the prestigious Edmond J. Safra Clinical Research Fellowship in Movement Disorders at UCL. During her fellowship, she refined her clinical expertise in rare movement disorders and pursued her research activities in neurogenetics, which culminated in the discovery of a new gene implicated in early-onset Parkinson’s disease and parkinsonism. For preliminary results on this gene, she was awarded the MJFF Edmond J. Safra Movement Disorders Research Career Development Award 2023.
Dr Magrinelli currently works as a Locum Consultant Neurologist at the National Hospital for Neurology and Neurosurgery, London, United Kingdom, and as a Postdoctoral Researcher in neurogenetics at the UCL Queen Square Institute of Neurology. Her main research interests focus on the clinical, genetic, and translational aspects of monogenic movement disorders. She is dedicated to gene discovery and validation, deep phenotyping, genotype-phenotype correlations and experimental approaches towards precision medicine. She has published over 80 peer-reviewed articles on these topics.
Objective:
To establish how genetic defects in PSMF1 cause neuronal death.
Background:
Understanding genetic forms of PD have unveiled biological mechanisms that are relevant to non-genetic forms of PD as well. I identified PSMF1 as a new gene associated with early-onset PD and parkinsonism in multiple families. The function of PSMF1 in neurons is unknown.
Methods/Design:
We will explore the effects of PSMF1 defects on the functions of mitochondria and proteasomes in participant-derived fibroblasts. Fibroblasts from 3 patients with PSMF1-related disorder and 3 healthy controls available in the UCL biobank will be compared. Next, we will generate neuronal models carrying genetic defects in PSMF1 to investigate how this causes neuronal death. Finally, we aim to generate mice modified with the mutated PSMF1 gene to assess their symptoms, look at their brain under the microscope, and test potential therapies.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This project will unveil biological mechanisms underpinning a new genetic form of PD which likely also contributes to sporadic forms of PD. By uncovering how PMSF1 causes disease, new drug development targets will be identified. In addition, if experiments aimed at enhancing or rescuing PSMF1 function in mice with genetic defects in PSMF1 show improvement or suppression of their symptoms, we will have proof of concept for PSMF1 gene therapy (i.e. the delivery of a normal copy of the defective gene inside a non-active, harmless virus) in humans.