Cytoplasmic Human TDP-43 Mislocalization Induces Widespread Dendritic Spine Loss in Mouse Upper Motor Neurons
| Autor: | Marcus S Dyer, Adele Woodhouse, Catherine A. Blizzard |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
amyotrophic lateral sclerosis Dendritic spine TDP-43 Dendrite RNA-binding protein Neurosciences. Biological psychiatry. Neuropsychiatry Biology Article dendrite spine 03 medical and health sciences 0302 clinical medicine mental disorders medicine Amyotrophic lateral sclerosis General Neuroscience Wild type nutritional and metabolic diseases medicine.disease nervous system diseases 030104 developmental biology medicine.anatomical_structure Cytoplasm Excitatory postsynaptic potential Neuroscience Nucleus 030217 neurology & neurosurgery RC321-571 |
| Zdroj: | Brain Sciences; Volume 11; Issue 7; Pages: 883 Brain Sciences Brain Sciences, Vol 11, Iss 883, p 883 (2021) |
| ISSN: | 2076-3425 |
| DOI: | 10.3390/brainsci11070883 |
| Popis: | Amyotrophic lateral sclerosis (ALS) is defined by the destruction of upper- and lower motor neurons. Post-mortem, nearly all ALS cases are positive for cytoplasmic aggregates containing the DNA/RNA binding protein TDP-43. Recent studies indicate that this pathogenic mislocalization of TDP-43 may participate in generating hyperexcitability of the upper motor neurons, the earliest detectable change in ALS patients, yet the mechanisms driving this remain unclear. We investigated how mislocalisation of TDP-43 could initiate network dysfunction in ALS. We employed a tetracycline inducible system to express either human wildtype TDP-43 (TDP-43WT) or human TDP-43 that cannot enter the nucleus (TDP-43ΔNLS) in excitatory neurons (Camk2α promoter), crossed Thy1-YFPH mice to visualize dendritic spines, the major site of excitatory synapses. In comparison to both TDP-43WT and controls, TDP-43ΔNLS drove a robust loss in spine density in all the dendrite regions of the upper motor neurons, most affecting thin spines. This indicates that TDP-43 is involved in the generation of network dysfunction in ALS likely through impacting the formation or durability of excitatory synapses. These findings are relevant to the vast majority of ALS cases, and provides further evidence that upper motor neurons may need to be protected from TDP-43 mediated synaptic excitatory changes early in disease. |
| Databáze: | OpenAIRE |
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