Alpha-synuclein (aSyn) is a cytosolic 140 amino acids protein and maintaining its cellular level is pivotal to preventing neuronal cell death. In health, aSyn is enriched in the presynaptic terminal and known to interact with the VAMP2 protein responsible for neurotransmission, although the outcomes in neurotransmission are elusive. On the other hand, in Parkinson’s disease patients, aSyn and its aggregate which is composed with organellar membranes and biomolecules are found in the soma and overall neurons. Indeed, emerging evidence suggests the secretion of aSyn aggregates depends on late endosomal/lysosomal VAMP7, which implies a possible aSyn-VAMP7 interaction. Several model systems have brought an invaluable understanding of aSyn and aggregates, yet none of them satisfy to be interpreted in cellulo context due to their extreme artificial condition. Altogether, with my recent publications and preliminary data, I establish hypotheses: i) organelle-specific lipid types and distribution define the aSyn aggregate, ii) VAMP7 interacts with aSyn, and iii) aSyn and aggregates distinctly impact neurotransmission and secretion. Accordingly, in this interdisciplinary project, I will 1) recreate each organellar membrane-dependent aSyn aggregate and systemically compare the physicochemical properties, 2) molecular dissect the aSyn-interacting domain of VAMP7, and 3) characterize the impact of aSyn and aggregates in neurotransmission and secretion by recapitulating the plasma membrane environment in great detail in my high-end 3D-printed membrane setup. Finally, I will 4) validate the outcomes in standard model membranes and bioengineered bacterial and eukaryotic cells.

Functional ultrasound imaging (fUS) reports changes of blood volume with a mesoscopic spatial resolution. It is used to image brain activity. However, the extent to which the fUS signal quantitatively reports local brain activation is unknown. We propose to characterize the cellular and vascular signals underlying fUS responses to odor, and to quantitatively model the link between these signals in control and CADASIL mice. First, we will use the olfactory bulb as a neurovascular model and compare the fUS signal from a single voxel to cellular and hemodynamic signals evoked by odor, and measured with 2-photon microscopy in the same co-registered brain volume. We will then establish the transfer functions (TFs) linking these signals and test the TF robustness to predict fUS signals from cellular responses. Finally, we will use CADASIL mice to validate TFs as quantitative tools to follow vascular dysfunction with aging, and assess the deficit correction with immunotherapy.

Psychosis is one of the mental disorders with the largest impact due to high personal and family costs. Building research at the very beginning of the psychotic process is crucial to give access to core pathophysiological features of the disease before all the pathological processes are fixed and before medication has side effects on brain function. Recent consensus work points to the need for further basic and therapeutic research in psychosis by applying a staging strategy that would differentiate the earliest stages such as Clinical High Risk for Psychosis (CHR-P) and the full blown First Episode of Psychosis (FEP) from later stages such as Schizophrenia. The direct application of this pathophysiological perspective is to identify the best markers predicting the progression of psychosis. However, while the pathophysiological aspects have been widely explored in schizophrenia, a major research effort is still needed to understand the underlying neural mechanisms and better predict the risk of psychosis progression in the earliest stages. Perceptual disturbances are key elements in the understanding of psychosis. In addition to clinically observed hallucinations and sensory distortions, there is now a large body of evidence for auditory and visual neurocognitive impairment in chronic psychosis. Concerning the early stages of psychosis, while sensory distortions are of high clinical value in assessing the risk of transition, there is still limited data on the underlying auditory or visual neurocognition. The aim of this project is to explore perceptual input and integrated processing in CHR-P patients, in comparison to first-episode psychosis patients and healthy volunteers. We hypothesize neurocognitive disturbances in the early stages, in relation to sensory distortions. We will explore visual processing, with tests measuring the processing of information as it enters the visual system, but also its transformation into a coherent whole, as in a face, as well as the way it is interpreted according to our expectations. We will also study auditory perception, with tests measuring the auditory perception of the input signal as well as the way certain sounds are interpreted in an emotional context. Finally, we will study the way time is perceived. A one-year follow-up in patients with CHR-P will measure whether specific sensory markers predict the risk of transition to psychosis. This project is based on the recruitment of a cohort of patients in four early intervention centres, all supported by research teams known for their works on perception. We will use proven markers of sensory functioning, which have been previously shown to be impaired in chronic psychosis. The research consortium is connected with the RHU Psycare network and will use its recruitment standards.

Mitochondria constitute a dynamic network whose morphology is conditioned by an equilibrium between fission and fusion events of their membranes. These processes are essential to shape the ultra-structure of the mitochondrial compartment and are thus also crucial for all mitochondrial functions. Consequently, defects in mitochondrial fusion and fission are associated with numerous pathologies. To modulate their membrane dynamics, mitochondria developed an evolutionary conserved strategy that involves large GTPases of the Dynamin-Related Proteins (DRPs) family. While the mechanism by which DRPs promote membrane fission is well understood, how they can also promote mixing of lipid bilayers remains unclear. MITOFUSION thus aims at dissecting how DRPs promote attachment and fusion of mitochondrial outer membranes. For this purpose, a multidisciplinary combination of approaches allying cell and structural biology, biophysics, biochemistry and bio-informatics methods will be employed.