Team 3 – RESEARCH INTEREST

“Welcome to Early stages of Parkinson’s disease”

MAP2/TGN-46/DAPI

Primary cortical neuron with staining for MAP2, TGN-46 and DAPI.

PPP2CA LRRK2

Primary cortical neuron with staining for PPP2CA and LRRK2.

CRISPR/Cas9

CRISPR/Cas9 technology used in the lab to silence or activate transcription in human cells: dCas9-mediated transcriptional modulation of phosphatases.
(A) dCas9 fused to effector domains can serve as an RNA-guided DNA-binding protein to target any protein to any DNA sequence. The effectors used with the catalytically inactive Cas9 (dCas9) are KRAB fusion protein to repress (CRISPRi) or the VP64 fusion protein to activate (CRISPRa) expression has shown on the picture.
(B) Stable suppression and overexpression of PPP1R1B by dCas9-KRAB or dCas9-VP64 in SH-SY5Y cells respectively. Cells stably expressing dCas9-KRAB or VP64 were infected with lentivirus constructs expressing a negative control sgRNA or two different sgRNAs targeting PPP1R1B.

Équipe Étapes précoces dans la maladie de Parkinson
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EARLY STAGES OF PARKINSON'S DISEASE

RESEARCH INTEREST

Our project is the following:

I- Towards a better definition of the clinical and biological phenotypes of the patients of our cohorts

II- Exploration of disturbed molecular events in Parkinson’s disease

I- Towards a better definition of the clinical and biological phenotypes of the patients of our cohorts

Our team aims to characterize the clinical and biological phenotypes of patients suffering from Parkinson’s disease (PD) from the early stages of the disease. Such researches should improve the diagnosis, help to better understand the pathophysiological mechanisms, to ultimately offer treatments that go beyond the symptomatic treatments that are offered today.

For this, we rely on the study of different cohorts established by the clinicians of our group within the Neurology and Movement Pathology Department of the CHU of Lille: sporadic cases or family cases of PD, patients with other Parkinsonian syndromes or other neurodegenerative diseases and healthy controls. For each subject, clinical data are collected (including elements such as exposure to environmental factors for pathophysiological purposes) and where appropriate therapeutic data are collected as well. Monitoring is provided for Parkinsonian patients.

In addition, we are studying, in particular at the molecular level, the biological samples collected from subjects in our cohorts. These cohorts are important for identifying novel clinical and biological features and reagents in a variety of settings, including at-risk individuals with deleterious mutations.

Many genetic factors contribute to the development of the disease and are studied in patients of our cohorts. This is the case for example of genes encoding alpha-synuclein (SNCA), LRRK2 and GBA which are found both in familial and sporadic forms of the disease.

Thanks to this fine characterization of the patients and the cellular models of human origin, we carried out unbiased analyzes by microchip transcriptomic approaches to identify the early dysfunctions and those present throughout the evolution of the disease.

In total, these data suggest an important role of cellular survival pathways, the participation of vesicular trafficking, inflammation processes, RNA perturbations and their translation into protein, in the development of Parkinson’s disease.

More refined analyzes of transcriptome study by RNAseq are underway to clarify these first results.

These jobs are based on research programs:

  • Programme hospitalier de recherche clinique (PHRC): Convergence.
  • Vaincre Alzheimer: eIF2 signaling and Splicing in Alzheimer and Parkinson’s disease (Collaboration Alzheimer Nederland: Wilma van de Berg, VUMC, Amsterdam, Hollande, Martin Figeac, plateforme de génomique fonctionnelle Lilloise).

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II- Exploration of disturbed molecular events

It seems important to better understand the disturbances identified by using experimental models (SNCA, LRRK2, pesticides) targeting the cell survival cascade leading to the identified disturbances and this on three axes aiming:

  • to better understand the involvement of EIF2 signaling and broad control of RNA translation in Parkinson’s disease
  • to modulate the cell survival cascade and some specific events such as membrane trafficking via a molecule-based approach in order to better decipher the cascade of events
  • to characterize and validate potential biomarkers associated with Parkinson’s disease.

This work is based on the following research programs:

  • JPND : Altered mRNA translation as a pathogenic mechanism across neurodegenerative diseases (collaborations: Storkebaum Erik, Radboud University, Nijmegen, Hollande (PI), Mallucci Giovanna, University of Cambridge, UK, Rosenblum Kobi, University of Haifa, Israel, Schuman Erin, Max Planck Institute for Brain Research, Frankfurt am Main Germany, Sonenberg Nahum, McGill University, Montreal Canada).
  • ANR: Defect in membrane trafficking in Parkinson’s disease (Collaboration: Thierry Galli Inserm, Paris (PI)).
  • France Parkinson: LRRK2 et altération de la traduction (Collaboration: Martin Figeac, Plateforme de génomique fonctionnelle et  Guillemette Marot plateforme de bioinformatique Bilille).
  • MJFF: Several projects on LRRK2 including LRRK2 phosphorylation (Collaborations : Veerle Bakelandt (KU Leuven, Belgium), Elisa Greggio (Univ Padova, Italy), Piet Herdewijn, Jeremy Nichols (Parkinson Institute, USA), Marc Cookson (NIH, USA), Sabine Hilfiker, (Granada, Spain)).
  • PEPS (Univ Lille, CNRS): ETD-MS/MS-Based detection of O-GLCNAC sites within alpha-synuclein (collaboration : Tony Lefebvre, Caroline Smet-Nocca, Lille).

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Conclusion: these projects aiming at a better understanding of Parkinson’s disease dysfunctions from the earlier stages should lead to fundamental advances in our understanding of disease mechanisms and ultimately to clinical benefits for patients.