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

Abstract

AbstractNeuronal 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.

Autoren

Dorothee Dormann
Anja Capell
Aaron M Carlson
Sunita S Shankaran
Ramona Rodde
Manuela Neumann
Elisabeth Kremmer
Takashi Matsuwaki
Keitaro Yamanouchi
Masugi Nishihara
Christian Haass

DOI

10.1111/j.1471-4159.2009.06211.x

eISSN

1471-4159

ISSN

0022-3042

Ausgabe der Veröffentlichung

3

Zeitschrift

Journal of Neurochemistry

Sprache

en

Online publication date

2009

Paginierung

1082 - 1094

Datum der Veröffentlichung

2009

Status

Published

Herausgeber

Wiley

Herausgeber URL

http://dx.doi.org/10.1111/j.1471-4159.2009.06211.x

Datum der Datenerfassung

2023

Titel

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

Ausgabe der Zeitschrift

110

Datenquelle: Crossref

Abstract

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.

Addresses

Deutsches Zentrum für Neurodegenerative Erkrankungen and Adolf-Butenandt-Institute, Department of Biochemistry, Ludwig-Maximilians-University, Munich, Germany.

Autoren

Dorothee Dormann
Anja Capell
Aaron M Carlson
Sunita S Shankaran
Ramona Rodde
Manuela Neumann
Elisabeth Kremmer
Takashi Matsuwaki
Keitaro Yamanouchi
Masugi Nishihara
Christian Haass

DOI

10.1111/j.1471-4159.2009.06211.x

eISSN

1471-4159

Externe Identifier

PubMed Identifier: 19522733

Open access

false

ISSN

0022-3042

Ausgabe der Veröffentlichung

3

Zeitschrift

Journal of neurochemistry

Schlüsselwörter

Cell Line, Tumor
Hela Cells
Animals
Mice, Knockout
Humans
Mice
Caspases
Intercellular Signaling Peptides and Proteins
DNA-Binding Proteins
Progranulins

Sprache

eng

Medium

Print-Electronic

Online publication date

2009

Paginierung

1082 - 1094

Datum der Veröffentlichung

2009

Status

Published

Datum der Datenerfassung

2009

Titel

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

Sub types

Comparative Study
Research Support, Non-U.S. Gov't
Journal Article

Ausgabe der Zeitschrift

110

Datenquelle: Europe PubMed Central

Abstract

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.

Autoren

Dorothee Dormann
Anja Capell
Aaron M Carlson
Sunita S Shankaran
Ramona Rodde
Manuela Neumann
Elisabeth Kremmer
Takashi Matsuwaki
Keitaro Yamanouchi
Masugi Nishihara
Christian Haass

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/19522733

DOI

10.1111/j.1471-4159.2009.06211.x

eISSN

1471-4159

Ausgabe der Veröffentlichung

3

Zeitschrift

J Neurochem

Schlüsselwörter

Animals
Caspases
Cell Line, Tumor
DNA-Binding Proteins
HeLa Cells
Humans
Intercellular Signaling Peptides and Proteins
Mice
Mice, Knockout
Progranulins

Sprache

eng

Country

England

Paginierung

1082 - 1094

PII

JNC6211

Datum der Veröffentlichung

2009

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2009

Titel

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

Sub types

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

110

Datenquelle: PubMed

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

Werkzeuge