Causes de la SLA et mécanismes de la dégénérescence motoneuronale

Research center

47 bld de l'Hôpital
75651 Paris
Alexis Brice


ED 158 3C


UMRS 1127 UMR 7225
IHU-A-ICM, Labex revive

Mots clefs

Amyotrophic Lateral Sclerosis (ALS)
motor neurons degeneration


Phenotype difference between ALS patients with expanded repeats in C9ORF72 and patients with mutations in other ALS-related genes. Millecamps S, Boillée S, Le Ber I, Seilhean D, Teyssou E, Giraudeau M, Moigneu C, Vandenberghe N, Danel-Brunaud V, Corcia P, Pradat PF, Le Forestier N, Lacomblez L, Bruneteau G, Camu W, Brice A, Cazeneuve C, Leguern E, Meininger V, Salachas F. J Med Genet. 2012 Apr;49(4):258-63.

Novel UBQLN2 mutations linked to amyotrophic lateral sclerosis and atypical hereditary spastic paraplegia phenotype through defective HSP70-mediated proteolysis. Teyssou E, Chartier L, Amador MD, Lam R, Lautrette G, Nicol M, Machat S, Da Barroca S, Moigneu C, Mairey M, Larmonier T, Saker S, Dussert C, Forlani S, Fontaine B, Seilhean D, Bohl D, Boillée S, Meininger V, Couratier P, Salachas F, Stevanin G, Millecamps S. Neurobiol Aging. 2017 Oct;58:239.e11-239.e20

System xC- is a mediator of microglial function and its deletion slows symptoms in amyotrophic lateral sclerosis mice. Mesci P, Zaïdi S, Lobsiger CS, Millecamps S, Escartin C, Seilhean D, Sato H, Mallat M, Boillée S. Brain. 2015 Jan;138(Pt 1):53-68.

C1q induction and global complement pathway activation do not contribute to ALS toxicity in mutant SOD1 mice. Lobsiger CS, Boillée S, Pozniak C, Khan AM, McAlonis-Downes M, Lewcock JW, Cleveland DW. Proc Natl Acad Sci U S A. 2013 Nov 12;110(46):E4385-92.

The NADPH oxidase Nox2 regulates VEGFR1/CSF-1R-mediated microglial chemotaxis and promotes early postnatal infiltration of phagocytes in the subventricular zone of the mouse cerebral cortex. Lelli A, Gervais A, Colin C, Chéret C, Ruiz de Almodovar C, Carmeliet P, Krause KH, Boillée S, Mallat M. Glia. 2013 Sep;61(9):1542-55.


Fields of research

Neurological and psychiatric diseases

Research Theme

Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset motor neuron disease. Although mostly sporadic, major geneticcauses are nucleotide expansions in C9ORF72 and mutations in SOD1, TARDBP and FUS. We have shown that motor neuron deathis non-cell autonomous and that reducing mutant SOD1 in CNS microglia/peripheral macrophages slows disease progression. This suggests that in ALS, mutant gene expression in microglia/macrophages as well as the natural activation response of these cellsbecome deleterious. As ALS is mainly sporadic, thus diagnosed with symptoms already present, acting on disease progression bymodulating microglia/macrophages could benefit all ALS cases.

Our first aim is to find how microglia/ macrophages participate to the disease. Importantly, the specific disease contribution ofperipheral macrophages, easier to reach than CNS microglia to reduce motor neuron loss, is unknown. In addition, targeting peripheral macrophages would be especially relevant and original to ALS as the biggest part of spinal motor neurons, the axon, liesoutside the CNS. We therefore ask how peripheral macrophages compared to CNS microglia are implicated in ALS and define theirdisease modifying capacity. Approaches include analyzing pathways activated during disease in peripheral nerve macrophages andblood monocyte/macrophages of ALS mice and patients and assessing toxicity of macrophages carrying different ALS mutations towards motor neurons using iPSc and mouse models.

Our second aim is to assess the crucial question whether different ALS genes lead to motor neuron death and deleteriousmicroglia/macrophage responses by gain or loss of function mechanisms. A major focus will be on newly discovered and theremaining unknown ALS genes with approaches including novel mouse modeling and gene discovery.Our project relies on the combined capacities of 4 PIs and 2 supporting clinicians forming this ALS team. The combined expertiseranges from cellular and molecular studies in animal models to use of human derived iPSc cell culture modeling and human geneticsas well as human postmortem tissue analysis. Results will contribute to basic understanding