Reversible induction of TDP-43 granules in cortical neurons after traumatic injury
| Autor: | Lilla Tar, Luc Dupuis, Albert C. Ludolph, Akila Chandrasekar, William Tsao, Philip C. Wong, Birgit Linkus, Francesco Roselli, Florian olde Heuvel, Diana Wiesner |
|---|---|
| Přispěvatelé: | University of Ulm (UUlm), Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Johns Hopkins University School of Medicine [Baltimore], Dieterle, Stéphane |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pathology TDP-43 [SDV]Life Sciences [q-bio] Cortical injury Mice Superoxide Dismutase-1 0302 clinical medicine Brain Injuries Traumatic MESH: Behavior Animal MESH: Animals Amyotrophic lateral sclerosis MESH: Amyotrophic Lateral Sclerosis MESH: Superoxide Dismutase-1 Motor Neurons Behavior Animal MESH: RNA-Binding Protein FUS Motor Cortex Immunohistochemistry DNA-Binding Proteins [SDV] Life Sciences [q-bio] Traumatic injury medicine.anatomical_structure Neurology MESH: Motor Neurons Motor cortex Genetically modified mouse medicine.medical_specialty MESH: Mice Transgenic Traumatic brain injury SOD1 MESH: Brain Injuries Traumatic Mice Transgenic MESH: Cytoplasmic Granules Biology Cytoplasmic Granules MESH: Motor Cortex 03 medical and health sciences Developmental Neuroscience Autophagy medicine Animals MESH: Autophagy MESH: Mice Amyotrophic Lateral Sclerosis Colocalization MESH: Immunohistochemistry medicine.disease nervous system diseases Disease Models Animal 030104 developmental biology RNA-Binding Protein FUS ALS MESH: Disease Models Animal MESH: DNA-Binding Proteins 030217 neurology & neurosurgery |
| Zdroj: | Experimental Neurology Experimental Neurology, 2018, 299 (Pt A), pp.15-25. ⟨10.1016/j.expneurol.2017.09.011⟩ Experimental Neurology, Elsevier, 2018, 299 (Pt A), pp.15-25. ⟨10.1016/j.expneurol.2017.09.011⟩ |
| ISSN: | 0014-4886 1090-2430 |
| DOI: | 10.1016/j.expneurol.2017.09.011 |
| Popis: | International audience; Traumatic brain injury (TBI) has been proposed as a risk factor for neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). To determine whether TBI might trigger or exacerbate ALS-relevant pathology, we delivered a mild stab-wound injury to the motor cortex of three different ALS mouse models expressing mutations in SOD1, TDP-43 or FUS and scrutinized the effects on the formation of phospho-TDP-43 (pTDP-43) cytoplasmic granules. Stab-injury induced the formation of cytoplasmic TDP-43 granules in wt animals, peaking at 3dpi; a much larger response was seen in mutant TDP-43 mice, whose response peaked at 7dpi. The pTDP-43 granules did not colocalize with the stress markers TIAR-1 and FUS but colocalized with FMRP (35%) and with p62 (65%), suggesting their involvement in transport granules and their clearance by autophagy. A similar, albeit smaller effect, was seen in mutant FUS mice. In the SOD1G93A mouse model, neither increase in pTDP-43 granules nor in SOD1 aggregates were detected. In all cases, pTDP-43 granules were cleared and the number of pTDP-43-positive neurons returned to baseline by 40dpi. Neither injury-related neuronal loss nor motor performance or survival was significantly different in transgenic mice receiving injury vs sham mice. Thus, trauma can trigger ALS-related TDP-43 pathology, the extent of which is modulated by ALS-related mutations. However, the pathological findings prove reversible and do not affect disease progression and neuronal vulnerability. |
| Databáze: | OpenAIRE |
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