Mutant TDP-43 Expression Triggers TDP-43 Pathology and Cell Autonomous Effects on Primary Astrocytes: Implications for Non-cell Autonomous Pathology in ALS
| Autor: | Philip M Beart, Chew L. Lau, Mathew D. F. Chiam, Samantha K. Barton, Bradley J. Turner, Hakan Muyderman, Doris Tomas |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Pathology medicine.medical_specialty Leupeptins Transgene Mutant SOD1 Gene Expression Mice Transgenic Cysteine Proteinase Inhibitors Biochemistry Superoxide dismutase 03 medical and health sciences Cellular and Molecular Neuroscience Mice 0302 clinical medicine mental disorders medicine Animals Amyotrophic lateral sclerosis Cells Cultured biology Dose-Response Relationship Drug Amyotrophic Lateral Sclerosis nutritional and metabolic diseases General Medicine Motor neuron medicine.disease nervous system diseases DNA-Binding Proteins Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Cytoplasm Astrocytes Mutation biology.protein 030217 neurology & neurosurgery Astrocyte |
| Zdroj: | Neurochemical research. 45(6) |
| ISSN: | 1573-6903 |
| Popis: | Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) caused by mutations in superoxide dismutase 1 (SOD1) is partly non-cell autonomous, involving cellular dysfunction of astrocytes. Whether non-cell autonomous effects occur in other forms of ALS, such as TAR DNA binding protein 43 (TDP-43)-related disease, remains unclear. Here, we characterised the impact of mutant TDP-43 expression on primary astrocytes derived from transgenic TDP-43A315T mice. Mutant TDP-43 astrocytes revealed evidence for TDP-43 pathology, shown by cytoplasmic TDP-43 inclusions and accumulation in insoluble cell fractions which was exacerbated by proteasomal inhibition. L-glutamate uptake, measured using an [3H]D-aspartate assay, was impaired in mutant TDP-43 astrocytes, while ATP accumulation was abnormal, suggesting mutant TDP-43 induced astrocytic dysfunction. Astrocyte activation coupled with spinal and cortical motor neuron loss in transgenic TDP-43A315T mice could imply non-cell autonomous effects of astrocytes in vivo. These data demonstrate mutant TDP-43-mediated cell autonomous effects on astrocytes that may contribute to motor neuron pathology in ALS. |
| Databáze: | OpenAIRE |
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