The key question our lab wants to answer is how previously healthy neurons start to die. To tackle this question, we investigate the molecular mechanisms involved in neuronal homeostasis as well as how these mechanisms are altered during the onset of neurodegeneration.

Neurodegenerative diseases are a major issue for Public Health in Europe and their prevalence will significantly increase worldwide. There is no treatment to cure of effectively reduce the progression for the most common neurodegenerative diseases like Alzheimer (AD) or Parkinson’s (PD). Hence, it is essential to understand the early events acting at the initial state of these diseases before irreversible neuronal damage occurs.

Our long-term goal is to decipher the molecular mechanism that trigger the onset of neurodegenerative disease and that are crucial to develop effective drugs that stop the progression of the disease.

Our investigations currently involved the following research axis:

1) Uncovering the regulation and function of autophagy in brain health and disease

Macroautophagy, hereafter called autophagy, is a highly conserved cellular self-devouring process by which proteins and organelles are degraded. The function of autophagy is essential for brain health and participates in synapse development, plasticity and even functions by likely controlling neurotransmission. Interestingly, our work shows that apart from classical amino acid deprivation, synaptic activity is crucial to activate autophagy in neurons. We aim to uncover the molecular mechanisms linking synaptic activity and the synaptic regulation of autophagy in the contexts of synaptic function, neuronal circuits, and animal behavior.

To fully understand how autophagy participate in brain function and safeguards neuronal survival we will also study the regulation and function of autophagy in glia. Glia support and protect neurons by regulating energy, protein and lipid homeostasis but the role of glia in neurodegeneration remains largely enigmatic. We are interested to understand how glial autophagy affects neuronal function and vice versa to ultimately uncover how dysfunctional autophagy in glia contributes to the onset of neurodegeneration.

2) To decipher the role of extracellular vesicles in maintaining brain function

Neuron and glia can communicate with each other via exosomes, a type of extracellular vesicles of endosomal origin, that can transport active biomolecules through the extracellular space to targets cells. Under physiological conditions, exosomes have beneficial functions, but under certain pathological conditions, they could accelerate the progression of neurodegenerative disease. Our lab seeks to further clarify the role of exosomes in synaptic function in the context of neuronal circuits and behaviors and how alterations of exosome release affect neurodegeneration and neuronal function. 

Recent evidence suggests a link between exosome release and autophagy in organism pathophysiology. We are interested to uncover the molecular interplay between autophagy and exosome release and the implication in brain function, aging and neurodegeneration.

3) Generation of genetic disease models in Drosophila to uncover molecular mechanism of neurodegenerative disease.

The “fruit fly” Drosophila melanogaster is a successful model to study molecular mechanism of neurodegeneration and other neurological disease. One objective of our lab is to further expand our collection of Drosophila disease models by generating new transgenic lines harboring corresponding human mutations or humanized fly models that express the human protein harboring pathological mutations. Together with our platform of behavior assays and diverse imaging techniques we have a pipeline to uncover how disease causative mutations and risk factors participate in Parkinson disease (PD), Alzheimer disease (AD), Frontotemporal dementia (FTD), Amyotrophic lateral sclerosis (ALS), Neurodegeneration with brain iron accumulation (NBIA)/ Beta-propeller protein-associated neurodegeneration (BPAN) and Epilepsy.

To fulfill these aims, we will use in addition to Drosophila ex vivo models like human neuron and glia cultures of immortalized cell lines and human induced pluripotent stem cells (iPSC).