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Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13318-23. doi: 10.1073/pnas.1008227107. Epub 2010 Jul 12.

ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS.

Author information

1
Ludwig Institute for Cancer Research and Department of Neuroscience, University of California at San Diego, La Jolla, CA 92093-0670, USA.

Abstract

Dominant mutations in two functionally related DNA/RNA-binding proteins, trans-activating response region (TAR) DNA-binding protein with a molecular mass of 43 KDa (TDP-43) and fused in sarcoma/translocation in liposarcoma (FUS/TLS), cause an inherited form of ALS that is accompanied by nuclear and cytoplasmic aggregates containing TDP-43 or FUS/TLS. Using isogenic cell lines expressing wild-type or ALS-linked TDP-43 mutants and fibroblasts from a human patient, pulse-chase radiolabeling of newly synthesized proteins is used to determine, surprisingly, that ALS-linked TDP-43 mutant polypeptides are more stable than wild-type TDP-43. Tandem-affinity purification and quantitative mass spectrometry are used to identify TDP-43 complexes not only with heterogeneous nuclear ribonucleoproteins family proteins, as expected, but also with components of Drosha microprocessor complexes, consistent with roles for TDP-43 in both mRNA processing and microRNA biogenesis. A fraction of TDP-43 is shown to be complexed with FUS/TLS, an interaction substantially enhanced by TDP-43 mutants. Taken together, abnormal stability of mutant TDP-43 and its enhanced binding to normal FUS/TLS imply a convergence of pathogenic pathways from mutant TDP-43 and FUS/TLS in ALS.

PMID:
20624952
PMCID:
PMC2922163
DOI:
10.1073/pnas.1008227107
[Indexed for MEDLINE]
Free PMC Article

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