Oct 20, 2019

Granulins modulate liquid-liquid phase separation and aggregation of TDP-43 C-terminal domain

BioRxiv : the Preprint Server for Biology
Anukool A BhopatkarVijayaraghavan Rangachari

Abstract

Tar DNA binding protein (TDP-43) has emerged as a key player in many neurodegenerative pathologies including frontotemporal lobar degeneration (FTLD) and amyotropic lateral sclerosis (ALS). Important hallmarks of FTLD and ALS are the toxic cytoplasmic inclusions of C-terminal fragments of TDP-43 (TDP-43CTD), which are formed upon proteolytic cleavage of full-length TDP-43 in the nucleus and subsequent transport to the cytoplasm. TDP-43CTD is also known to form stress granules (SGs) by coacervating with RNA in cytoplasm under stress conditions and are believed to be involved in modulating the pathologies. Among other factors affecting these pathologies, the pleiotropic protein called progranulin (PGRN) has gained significant attention lately. The haploinsufficiency of PGRN, caused by autosomal dominant mutations in GRN gene, results in its loss-of-function linked to FTLD and ALS. But precisely how the protein contributes to the pathology remains unknown. Recently, cleavage to GRNs were observed to be a significant part of FTLD and ALS progression with specific GRNs exacerbating TDP-43-induced toxicity in C.elegans. In this report, we show that GRNs -3 and -5 directly interact with TDP-43CTD to modulate aggregation or stress gran...Continue Reading

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Mentioned in this Paper

GRN gene
Caenorhabditis elegans
TARDBP
GRN
Cell Nucleus
Protein TDP-43
Toxic Effect
Grn protein, mouse
Protein Aggregation, Pathological
Terminal (End Postition)

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