Document Type

Article

Publication Date

1-6-2020

Department

Chemistry and Biochemistry

School

Mathematics and Natural Sciences

Abstract

Tar DNA binding protein 43 (TDP-43) has emerged as a key player in many neurodegenerative pathologies including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Hallmarks of both FTLD and ALS are the toxic cytoplasmic inclusions of the prion-like C-terminal fragments of TDP-43 (TDP-43 CTD), formed upon proteolytic cleavage of full-length TDP-43 in the nucleus and subsequent transport to the cytoplasm. Both full-length TDP-43 and its CTD are also known to form stress granules (SGs) by coacervating with RNA in the cytoplasm during stress and may be involved in these pathologies. Furthermore, mutations in PGRN gene, leading to haploinsufficiency and diminished function of progranulin (PGRN) protein, are strongly linked to FTLD and ALS. Recent reports have indicated that proteolytic processing of PGRN to smaller protein modules called granulins (GRNs) contributes to FTLD and ALS progression, with specific GRNs exacerbating TDP-43–induced cytotoxicity. Here, we investigated the interactions between the proteolytic products of both TDP-43 and PGRN. Based on structural disorder and charge distributions, we hypothesized that GRNs -3 and -5 could interact with TDP-43 CTD. We also show that in both reducing and oxidizing conditions GRNs -3 and -5 interact with and differentially modulate TDP-43 CTD aggregation and/or liquid-liquid phase separation (LLPS) in vitro. While GRN-3 promoted insoluble aggregates of TDP-43 CTD, GRN-5 mediated LLPS. These results constitute the first observation of an interaction between GRNs and TDP-43, suggesting a mechanism by which attenuated PGRN function could lead to familial FTLD or ALS.

Publication Title

Journal of Biological Chemistry

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