Phosphorylated and ubiquitinated TDP-43 pathological inclusions in ALS and FTLD-U are recapitulated in SH-SY5Y cells.

Abstract:

:We report phosphorylated and ubiquitinated aggregates of TAR DNA binding protein of 43 kDa (TDP-43) in SH-SY5Y cells similar to those in brains of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). Two candidate sequences for the nuclear localization signal were examined. Deletion of residues 78-84 resulted in cytoplasmic localization of TDP-43, whereas the mutant lacking residues 187-192 localized in nuclei, forming unique dot-like structures. Proteasome inhibition caused these to assemble into phosphorylated and ubiquitinated TDP-43 aggregates. The deletion mutants lacked the exon skipping activity of cystic fibrosis transmembrane conductance regulator (CFTR) exon 9. Our results suggest that intracellular localization of TDP-43 and proteasomal function may be involved in inclusion formation and neurodegeneration in TDP-43 proteinopathies.

journal_name

FEBS Lett

journal_title

FEBS letters

authors

Nonaka T,Arai T,Buratti E,Baralle FE,Akiyama H,Hasegawa M

doi

10.1016/j.febslet.2008.12.031

subject

Has Abstract

pub_date

2009-01-22 00:00:00

pages

394-400

issue

2

eissn

0014-5793

issn

1873-3468

pii

S0014-5793(08)01022-3

journal_volume

583

pub_type

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