Tweak regulates astrogliosis, microgliosis and skeletal muscle atrophy in a mouse model of amyotrophic lateral sclerosis

Melissa Bowerman; Céline Salsac; Emmanuelle Coque; Émilie Eiselt; Roman G Deschaumes; Alexandre Brodovitch; Linda C Burkly; Frédérique Scamps; Cédric Raoul

doi:10.1093/hmg/ddv094

Tweak regulates astrogliosis, microgliosis and skeletal muscle atrophy in a mouse model of amyotrophic lateral sclerosis

Hum Mol Genet. 2015 Jun 15;24(12):3440-56. doi: 10.1093/hmg/ddv094. Epub 2015 Mar 12.

Authors

Melissa Bowerman¹, Céline Salsac², Emmanuelle Coque¹, Émilie Eiselt², Roman G Deschaumes², Alexandre Brodovitch³, Linda C Burkly⁴, Frédérique Scamps², Cédric Raoul⁵

Affiliations

¹ The Neuroscience Institute of Montpellier (INM), Inserm UMR1051, Saint-Eloi Hospital, 80 rue Augustin Fliche, 34091 Montpellier, France, Montpellier University, Montpellier, France.
² The Neuroscience Institute of Montpellier (INM), Inserm UMR1051, Saint-Eloi Hospital, 80 rue Augustin Fliche, 34091 Montpellier, France.
³ Inserm UMR1067, Parc Scientifique et Technologique de Luminy, Marseille, France and.
⁴ Biogen Idec, Cambridge, MA, USA.
⁵ The Neuroscience Institute of Montpellier (INM), Inserm UMR1051, Saint-Eloi Hospital, 80 rue Augustin Fliche, 34091 Montpellier, France, [email protected].

PMID: 25765661
DOI: 10.1093/hmg/ddv094

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that primarily affects motoneurons in the brain and spinal cord. Astrocyte and microglia activation as well as skeletal muscle atrophy are also typical hallmarks of the disease. However, the functional relationship between astrocytes, microglia and skeletal muscle in the pathogenic process remains unclear. Here, we report that the tumor necrosis factor-like weak inducer of apoptosis (Tweak) and its receptor Fn14 are aberrantly expressed in spinal astrocytes and skeletal muscle of SOD1(G93A) mice. We show that Tweak induces motoneuron death, stimulates astrocytic interleukin-6 release and astrocytic proliferation in vitro. The genetic ablation of Tweak in SOD1(G93A) mice significantly reduces astrocytosis, microgliosis and ameliorates skeletal muscle atrophy. The peripheral neutralization of Tweak through antagonistic anti-Tweak antibody ameliorates muscle pathology and notably, decreases microglial activation in SOD1(G93A) mice. Unexpectedly, none of these approaches improved motor function, lifespan and motoneuron survival. Our work emphasizes the multi-systemic aspect of ALS, and suggests that a combinatorial therapy targeting multiple cell types will be instrumental to halt the neurodegenerative process.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis / genetics*
Amyotrophic Lateral Sclerosis / metabolism
Amyotrophic Lateral Sclerosis / pathology*
Animals
Antigens, CD / metabolism
Antigens, Differentiation, Myelomonocytic / metabolism
Astrocytes / metabolism
Astrocytes / pathology
CD163 Antigen
Cell Death
Cell Proliferation
Cytokine TWEAK
Disease Models, Animal
Gene Deletion
Gene Expression Regulation
Gliosis / genetics*
Interleukin-6 / biosynthesis
Life Expectancy
Mice
Mice, Knockout
Mice, Transgenic
Microglia / metabolism
Microglia / pathology
Motor Endplate / genetics
Motor Endplate / metabolism
Motor Neurons / metabolism
Motor Neurons / pathology
Muscle, Skeletal / metabolism*
Muscle, Skeletal / pathology*
Muscular Atrophy / genetics*
Mutation
Receptors, Cell Surface / metabolism
Receptors, Tumor Necrosis Factor / genetics
Receptors, Tumor Necrosis Factor / metabolism
Signal Transduction
Spinal Cord / metabolism
Superoxide Dismutase / genetics
Superoxide Dismutase-1
TWEAK Receptor
Tumor Necrosis Factors / genetics*
Tumor Necrosis Factors / metabolism
Up-Regulation

Substances

Antigens, CD
Antigens, Differentiation, Myelomonocytic
CD163 Antigen
Cytokine TWEAK
Interleukin-6
Receptors, Cell Surface
Receptors, Tumor Necrosis Factor
TWEAK Receptor
Tnfrsf12a protein, mouse
Tnfsf12 protein, mouse
Tumor Necrosis Factors
Sod1 protein, mouse
Superoxide Dismutase
Superoxide Dismutase-1