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Role of microglial cells during neurodegeneration in Amyotrophic Lateral Sclerosis

Final Report Summary - MICROGLIA IN ALS (Role of microglial cells during neurodegeneration in Amyotrophic Lateral Sclerosis)

When the Marie Curie funding started, the Principal Investigator working on the project, Dr Severine Boillee was coming back from a post-doc in the United States, in the laboratory of Pr. Don W Cleveland in San Diego, CA. The Marie Curie funding has allowed her to get and set up all the necessary tools to start the project.
Scientific progress:
The project main goal was to find means to slow down the progression of Amyotrophic Lateral Sclerosis (ALS) disease. ALS is the most common adult-onset motor neuron disease leading to paralysis and death of the patients within 2-5 years after the diagnosis without treatment actually available to stop the progressive motor neuron degeneration. During her post-doc, Dr Boillee’s work showed that microglial cells, the macrophages of the central nervous system/ macrophages, were participating to the disease progression. Since most of ALS cases are sporadic, and therefore diagnosed when the symptoms are already apparent, the purpose of this project was to target the phase of the disease the most relevant for the majority of ALS cases, the symptomatic disease phase. Using the model that recapitulates the best ALS symptoms, mice and rats expressing mutant Cu/Zn superoxide dismutase (SOD1, the second most frequent cause for familial ALS) we addressed the three following specific aims to analyze the microglia/ motor neuron interaction, to understand how microglial cells/ macrophages participate to the disease and to find ways to slow down the symptomatic phase of the disease. We studied (1) the mechanisms of microglial neurotoxicity (2) the signals coming from motor neurons that could activate and attract microglial cells and (3) the participation of macrophages at the periphery compared to CNS microglia to motor neuron degeneration in ALS models. The main scientific results obtained during the Marie Curie funding were the following. Concerning Aim 1, we have shown that the complement system (implicated in the immune response) was a good candidate as a microglial/macrophage to motor neuron neurotoxic interaction however, we showed that although the complement system had previously been implicated in neurodegenerative processes in other neurodegenerative diseases (Alzheimer’s and Parkinson’s models) it was not implicated in ALS disease in mice. We have also focused on the implication of microglial glutamate by studying the expression and function of the cystine/glutamate antiporter, system xc-. We have shown that system xc- participated in the progression of the disease and motor neuron degeneration in ALS mice. With our second aim, we have focused on the family of chemokines, cytockines potent to attract macrophages to reveal pathway potentially implicated in the attraction of microglial cells around affected motor neurons. We have shown that the chemokine/chemokine receptor couple CXCL12/CXCR4 could be a candidate in ALS models. For our third aim, we have set up a technique to be able to replace macrophages at the periphery without interfering with microglial cells in the spinal cord and the brain. We have used this technique to be able to analyze the participation of peripheral macrophages in ALS mouse models.
This project has therefore revealed different pathways implicated in motor neuron / microglial communication and to target to slow the motor neuron degenerating process during the progression of the disease in ALS mice. As microglial cells are activated both in familial and sporadic ALS, these findings could provide a foundation for discovery of general pathways of motor neuron disease and open up ways to identify new targets for development of therapies.
Deliverables:
Several papers directly linked to the project are in the process of being published. One paper is in favorable revision at PNAS (Aim 1-1, SB co-1st author), one review on the microglia in ALS subject (SB last author), two papers in preparation (SB last author, Aim 1-2 Pinar Mesci 1st author and Aim 2 Ana Barbeito 1st author) and one paper still in progress (SB last author, Sakina Zaidi main author).
Collaborations:
To develop the project, I have set up collaborations with different scientists including Don W Cleveland (San Diego, USA), John Yates (San Diego, USA), Hideyo Sato (Yamagata, Japan), Stephanie Millecamps (ICM, France), Christian Lobsiger (ICM, France), Carole Escartin (CEA, France), Annabelle Reaux- Le-Goazigo (Institut de la vision, France), which have been implicated in the project and contributed to the papers currently in preparation. In addition, we have published 5 papers not directly related to the Marie Curie project in Neurobiol Aging (2 papers, SB 2nd and 4th author), J Med Genet (SB 2nd author), Acta Neuropathol (SB 4th author), Glia (SB 2nd-last author).
Management:
To fulfill the scientific objectives of the project, the PI has hired different collaborators including 2 Master’s students, 2 Phd students and a technician. This project has led to one thesis defended with honors and a second thesis that will be defended later this year. Both PhD students want to pursue a career in science. Dr Ana Barbeito has obtained a postdoctoral fellowship to return in her native country (Uruguay) to afterwards be able to apply to a university position. Pinar Mesci is currently finishing her thesis and is currently applying to different laboratories mainly in the US and in the UK for a post-doc position. We have acquired the funding necessary to support the salaries of these collaborators (one French Ministry of research PhD fellowship, one Ecole des Neuroscience PhD fellowship, 2 Fondation pour la recherche medicale 4th year PhD fellowship, a grant from the ALS Thierry Latran foundation (TLF), supporting the salary of Sakina Zaidi). We have also acquired additional funding for the project (equipment: laser microdissector through a Fondation pour la Recherche sur le Cerveau grant and consumables through a TLF funding and French ALS association).
Prize:
Dr Severine Boillee (together with Pr V. Meininger) has been the recipient of the NRJ-foundation de France Prize in 2011 (recognizing a scientist in the field of neuroscience each year).
Dissemination:
Dr S. Boillee has been invited to give 9 seminars in French and European labs and to present her work to 8 international meetings.
During the period of the funding, she became a member of the scientific board of the Thierry Latran Foundation (European ALS) and French ALS association and of the scientific program committee of the ENCALS (European Network for the Cure of ALS) yearly meeting.
Career development:
At the beginning of the project, Dr S. Boillee was on a one year trainee position at the INSERM and she acquired a life-time scientist position at the INSERM (CR2 level). She afterwards got promoted to the next level (CR1 position), last step before being able to apply to a Professor position at the INSERM. This last year, she has applied to become a group leader (in the institute where she moved in 2 years ago, Brain and Spinal cord institute, ICM, in Paris). Starting beginning of 2014, she will lead a team composed of 4 Principal Investigators and their students, dedicated to ALS.