Astrocytic expression of TDP-43 results in non-cell autonomous changes
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Abstract
TAR DNA binding protein 43 (TDP-43) is a heterogeneous nuclear ribonucleoprotein that regulates gene expression, RNA stability, and is involved in shuttling back and forth from the nucleus to the cytoplasm. TDP-43 is predominantly localized to the nucleus. Glial Fibrillary Acidic Protein (GFAP) is a major astrocyte marker whose expression increases when astrocytes are activated. We have developed a mouse model that selectively and conditionally expresses a defective nuclear localization signal of TDP-43 (NLS) under control of the astrocytic GFAP promoter to investigate pathological outcomes and non-cell autonomous effects of TDP-43 mis-expression. We hypothesize that GFAP/TDP-43NLS mice will show non-cell autonomous changes in neurons caused by expression of TDP-43NLS in astrocytes. In order to characterize this model of astrocyte expression, an exon array was used to examine global changes in RNA expression/splicing in the spinal cord of two-month old mice. In addition, immunohistochemistry in both two-month old and six-month-old mice reveal age-dependent changes in myelin basic protein. At two months of age GFAP/TDP-43NLS mice display functional changes in memory, which may be associated with the changes in myelination observed. Primary cortical neuron/astrocyte co-cultures expressing TDP-43NLS exclusively in astrocytes show a significant decrease in neurons (as shown by III-tubulin immunoreactivity) compared with littermate controls. These data suggest that astrocytic expression of TDP-43NLS alters neuronal function both in vitro and in vivo. This study may provide insight and a better understanding of how astrocytic accumulation/aggregation of TDP-43 contributes to neurodegeneration.