AGE-DEPENDENT MISLOCALISATION OF TDP-43 IN HUMAN CORTICAL ORGANOTYPIC SLICE CULTURE

Transactive response DNA binding protein 43 kDa (TDP-43) is an important nuclear RNA/DNA-binding protein involved in the regulation of RNA processing and homeostasis. However, in many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), TDP-43 mislocalises from the nucleus to cytoplasm triggering a range of downstream pathways that ultimately lead to cell death.
Our objective was to develop a TDP-43 proteinopathy model using adult human cortical organotypic slice (HCOS) cultures in tissue obtained from patients undergoing neurosurgical procedures. Human cortical samples are obtained from patients aged 18-80 years from frontal and temporal cortex with full ethical approval. Slice cultures were prepared and maintained for up to 21 days in vitro (DIV). We found that over time in culture in tissue from older (>55 years) patients TDP-43 spontaneously mislocalised from the nucleus to the cytoplasm. However, in young (<35 years) patients there was significantly less TDP-43 mislocalisation. Investigating this early TDP-43-related pathology we also found an increase in stress granule (TIA1) and DNA damage markers, and increased phosphorylated TDP-43 (Ser409/410) expression in the cortical tissue from the older patients.
Our data, therefore, suggests that HCOS from older patients can mimic some of the hallmark pathophysiological features associated with TDP-43-related proteinopathy and we are now investigating the time course of these changes in further detail.