Proteolytic processing of TAR DNA binding protein‐43 by caspases produces C‐terminal fragments with disease defining properties independent of progranulin

Neuronal and glial deposition of misfolded, proteolytically processed, polyubiquitinated and abnormally phosphorylated C‐terminal fragments (CTFs) of the TAR DNA binding protein‐43 (TDP‐43) is a pathological hallmark of frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD‐U) an...

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Veröffentlicht in:Journal of neurochemistry 2009-08, Vol.110 (3), p.1082-1094
Hauptverfasser: Dormann, Dorothee, Capell, Anja, Carlson, Aaron M., Shankaran, Sunita S., Rodde, Ramona, Neumann, Manuela, Kremmer, Elisabeth, Matsuwaki, Takashi, Yamanouchi, Keitaro, Nishihara, Masugi, Haass, Christian
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container_issue 3
container_start_page 1082
container_title Journal of neurochemistry
container_volume 110
creator Dormann, Dorothee
Capell, Anja
Carlson, Aaron M.
Shankaran, Sunita S.
Rodde, Ramona
Neumann, Manuela
Kremmer, Elisabeth
Matsuwaki, Takashi
Yamanouchi, Keitaro
Nishihara, Masugi
Haass, Christian
description Neuronal and glial deposition of misfolded, proteolytically processed, polyubiquitinated and abnormally phosphorylated C‐terminal fragments (CTFs) of the TAR DNA binding protein‐43 (TDP‐43) is a pathological hallmark of frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD‐U) and certain cases of amyotrophic lateral sclerosis. We demonstrate that TDP‐43 can be proteolytically processed by caspases upon induction of apoptosis to a major 35 kDa and a minor 25 kDa CTF. These fragments are initially soluble, but over time they accumulate as insoluble and pathologically phosphorylated derivatives. However, proteolytic processing appears not to be absolutely required for the deposition of insoluble TDP‐43 species, since a caspase resistant mutant of TDP‐43 is also converted into insoluble species. Phosphorylation at S409/410 apparently occurs late during the conversion of soluble to insoluble TDP‐43, suggesting that phosphorylation is not a prerequisite for aggregation. Loss of function of the progranulin (PGRN) gene causes FTLD‐U with TDP‐43 positive inclusions and has been suggested to lead to caspase activation and subsequent TDP‐43 processing. However, siRNA‐mediated knockdown of PGRN in cell culture as well as a PGRN gene knockout in mice failed to cause the formation of the disease characterizing CTFs of TDP‐43. Our findings therefore suggest that caspase‐mediated processing generates CTFs of similar biochemical properties as those occurring in nuclear and cytoplasmic deposits of FTLD‐U patients independent of PGRN levels.
doi_str_mv 10.1111/j.1471-4159.2009.06211.x
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subjects Animals
Biochemistry
Biological and medical sciences
Caspases - genetics
Caspases - metabolism
Cell Line, Tumor
Cerebrospinal fluid. Meninges. Spinal cord
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
dementia
Deoxyribonucleic acid
DNA
DNA-Binding Proteins - deficiency
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
frontotemporal lobar degeneration
FTLD‐U
HeLa Cells
Humans
Intercellular Signaling Peptides and Proteins - deficiency
Intercellular Signaling Peptides and Proteins - genetics
Intercellular Signaling Peptides and Proteins - metabolism
Medical sciences
Mice
Mice, Knockout
Nervous system (semeiology, syndromes)
neurodegeneration
Neurology
progranulin
Protein folding
Proteins
TAR DNA binding protein‐43
title Proteolytic processing of TAR DNA binding protein‐43 by caspases produces C‐terminal fragments with disease defining properties independent of progranulin
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