Glial TDP‐43 and TDP‐43 induced glial pathology, focus on neurodegenerative proteinopathy syndromes

Since its discovery in 2006, TAR DNA binding protein 43 (TDP‐43) has driven rapidly evolving research in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic predominant age‐related TDP‐43 encephalopathy (LATE). TDP‐43 mislocalization or aggregation is the hallmark of TDP‐43 proteinopathy and is associated with cognitive impairment that can be mapped to its regional deposition. Studies in human tissue and model systems demonstrate that TDP‐43 may potentiate other proteinopathies such as the amyloid or tau pathology seen in Alzheimer's Disease (AD) in the combination of AD+LATE. Despite this growing body of literature, there remain gaps in our understanding of whether there is heterogeneity in TDP‐43 driven mechanisms across cell types. The growing observations of correlation between TDP‐43 proteinopathy and glial pathology suggest a relationship between the two, including pathogenic glial cell‐autonomous dysfunction and dysregulated glial immune responses to neuronal TDP‐43. In this review, we discuss the available data on TDP‐43 in glia within the context of the neurodegenerative diseases ALS and FTLD and highlight the current lack of information about glial TDP‐43 interaction in AD+LATE. TDP‐43 has proven to be a significant modulator of cognitive and neuropathological outcomes. A deeper understanding of its role in diverse cell types may provide relevant insights into neurodegenerative syndromes. MAIN POINTS: Pathologic accumulation of TDP‐43 (red clusters in image) in neurons (pink) and glia (purple, green, and yellow) may lead to toxicity and loss of TDP‐43 function. Given the importance of glia in neurodegeneration, there is a need to better define the role of TDP‐43 in glial mediated disease mechanisms.