TDP‐35 sequesters TDP‐43 into cytoplasmic inclusions through binding with RNA

Abstract

Edited by Barry HalliwellKeywords: TAR DNA binding protein of 43kDa C-terminal fragment of $35kDa Sequestration Cytoplasmic inclusion RNA recognition motif a b s t r a c t TDP-43 (TAR DNA binding protein of 43kDa) and its C-terminal fragments are thought to be linked to the pathologies of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Here, we demonstrate that the aggregates or inclusions formed by its 35-kDa fragment (namely TDP-35) sequester full-length TDP-43 into cytoplasmic inclusions; and this sequestration is mediated by binding with RNA that is enriched in the cytoplasmic inclusions. RNA recognition motif 1 (RRM1) of TDP-43/TDP-35 plays a dominant role in nucleic-acid binding; mutation in this moiety abrogates formation of the TDP-35 inclusions and its RNA-assisted association with TDP-43. Thus, TDP-35 is able to sequester TDP-43 from nuclear localization into cytoplasmic inclusions, and RNA binding plays an essential role in this process.

The phosphatase calcineurin regulates pathological TDP-43 phosphorylation

“…3a). TDP-35 has been previously observed in human disease, and has been demonstrated to promote aggregation and recruit TDP-43 into inclusions [8, 9, 22]. To determine whether activation of calcineurin is protective, we treated HEK293 cells with the metal ion Ni 2+ .…”

Structural Insights Into TDP-43 and Effects of Post-translational Modifications

“…An additional consistently observed aberration is the accumulation of fragmented TDP-43 in cytoplasmic aggregates (Neumann et al, 2006;Zhang et al, 2007Zhang et al, , 2009Che et al, 2015;Berning and Walker, 2019). These fragments appear to be the result of caspase cleavage at several sites (Figure 1).…”

“…These fragments appear to be the result of caspase cleavage at several sites (Figure 1). Cleavage at D89-A90 results in a 35 kDa fragment (TDP-35) that lacks the NTD and disrupts the NLS but is correctly folded (Che et al, 2015). Sites at D169-G170 and D174-C175 are both associated with the 25 kDa fragment (TDP-25) which lacks the NTD, NLS and most of RRM1 (Li et al, 2015;Chiang et al, 2016; Figure 3B).…”

Sequestration of cellular interacting partners by protein aggregates: implication in a loss‐of‐function pathology

“…Under cellular stress conditions, TDP‐43 assembles into cytoplasmic stress granules (SGs) and RNP complexes that contain RNA and RBPs . Our research showed that TDP‐35 triggers formation of cytoplasmic inclusions , which sequester full‐length TDP‐43 through binding with RNA , suggesting that RNA is critical for formation of inclusions and sequestration of TDP‐43.…”

“…The TDP‐43, FUS, and GGGGCC repeat expansion of C9orf72 contribute to the pathogenesis of ALS and FTLD; they are all associated with RNA and RNA‐binding proteins (RBPs) . Our studies revealed that the 35 kDa fragment of TDP‐43 (namely TDP‐35) forms inclusions in the cytoplasm and causes alteration of RNA processing , and even sequesters full‐length TDP‐43 into cytoplasmic inclusions from nucleus through binding with RNA . The C‐terminal mutants of FUS lacking the nuclear localization signal (NLS) are mislocalized in the cytoplasm and recruit hnRNP A1, hnRNP A2, wild‐type FUS, and some poly(A)‐binding proteins (PABPs) into the aggregates .…”