1. Disruption of the astrocytic TNFR1-GDNF axis accelerates motor neuron degeneration and disease progression in amyotrophic lateral sclerosis
- Author
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Eleonora Aronica, Daniela Rossi, Liliana Brambilla, Chiara F. Valori, Francesca Martorana, Giulia Guidotti, Anand Iyer, Brambilla, L, Guidotti, G, Martorana, F, Iyer, A, Aronica, E, Valori, C, Rossi, D, AII - Amsterdam institute for Infection and Immunity, Pathology, ANS - Cellular & Molecular Mechanisms, and APH - Amsterdam Public Health
- Subjects
0301 basic medicine ,Nervous system ,animal diseases ,Mice ,0302 clinical medicine ,Superoxide Dismutase-1 ,Sod1 protein, mouse ,Neurotrophic factors ,genetics [Glial Cell Line-Derived Neurotrophic Factor] ,Glial cell line-derived neurotrophic factor ,Amyotrophic lateral sclerosis ,Genetics (clinical) ,pathology [Astrocytes] ,Motor Neurons ,metabolism [Astrocytes] ,Neurodegeneration ,pathology [Nerve Degeneration] ,General Medicine ,Anatomy ,genetics [Superoxide Dismutase-1] ,genetics [Amyotrophic Lateral Sclerosis] ,medicine.anatomical_structure ,Spinal Cord ,Receptors, Tumor Necrosis Factor, Type I ,genetics [Nerve Degeneration] ,Disease Progression ,Signal Transduction ,metabolism [Spinal Cord] ,pathology [Motor Neurons] ,Central nervous system ,Mice, Transgenic ,pathology [Spinal Cord] ,Biology ,biosynthesis [Tumor Necrosis Factor-alpha] ,Transneuronal degeneration ,astrocytes, TNFR1, GDNF, ALS, motor neuron degeneration ,03 medical and health sciences ,ddc:570 ,Genetics ,medicine ,Animals ,Humans ,Glial Cell Line-Derived Neurotrophic Factor ,pathology [Amyotrophic Lateral Sclerosis] ,Molecular Biology ,genetics [Tumor Necrosis Factor-alpha] ,Tumor Necrosis Factor-alpha ,metabolism [Amyotrophic Lateral Sclerosis] ,Amyotrophic Lateral Sclerosis ,metabolism [Motor Neurons] ,Motor neuron ,medicine.disease ,030104 developmental biology ,nervous system ,Gene Expression Regulation ,Astrocytes ,Nerve Degeneration ,biosynthesis [Glial Cell Line-Derived Neurotrophic Factor] ,biology.protein ,genetics [Receptors, Tumor Necrosis Factor, Type I] ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Considerable evidence indicates that neurodegeneration in amyotrophic lateral sclerosis (ALS) can be conditioned by a deleterious interplay between motor neurons and astrocytes. Astrocytes are the major glial component in the central nervous system (CNS) and fulfill several activities that are essential to preserve CNS homeostasis. In physiological and pathological conditions, astrocytes secrete a wide range of factors by which they exert multimodal influences on their cellular neighbours. Among others, astrocytes can secrete glial cell line-derived neurotrophic factor (GDNF), one of the most potent protective agents for motor neurons. This suggests that the modulation of the endogenous mechanisms that control the production of astrocytic GDNF may have therapeutic implications in motor neuron diseases, particularly ALS. In this study, we identified TNF receptor 1 (TNFR1) signalling as a major promoter of GDNF synthesis/release from human and mouse spinal cord astrocytes in vitro and in vivo To determine whether endogenously produced TNFα can also trigger the synthesis of GDNF in the nervous system, we then focused on SOD1(G93A) ALS transgenic mice, whose affected tissues spontaneously exhibit high levels of TNFα and its receptor 1 at the onset and symptomatic stage of the disease. In SOD1(G93A) spinal cords, we verified a strict correlation in the expression of the TNFα, TNFR1 and GDNF triad at different stages of disease progression. Yet, ablation of TNFR1 completely abolished GDNF rises in both SOD1(G93A) astrocytes and spinal cords, a condition that accelerated motor neuron degeneration and disease progression. Our data suggest that the astrocytic TNFR1-GDNF axis represents a novel target for therapeutic intervention in ALS
- Published
- 2016