Disruption of the astrocytic TNFR1-GDNF axis accelerates motor neuron degeneration and disease progression in amyotrophic lateral sclerosis

Autor: Eleonora Aronica, Daniela Rossi, Liliana Brambilla, Chiara F. Valori, Francesca Martorana, Giulia Guidotti, Anand Iyer
Přispěvatelé: 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, APH - Amsterdam Public Health
Rok vydání: 2016
Předmět:
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
Zdroj: Human molecular genetics 25(14), ddw161 (2016). doi:10.1093/hmg/ddw161
Human molecular genetics, 25(14), 3080-3095. Oxford University Press
Europe PubMed Central
ISSN: 1460-2083
0964-6906
DOI: 10.1093/hmg/ddw161
Popis: 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
Databáze: OpenAIRE
Externí odkaz: