TDP-43 Loss-of-Function Causes Neuronal Loss Due to Defective Steroid Receptor-Mediated Gene Program Switching in Drosophilia

Lies Vanden Broeck; Marina Naval-Sánchez; Yoshitsugu Adachi; Danielle Diaper; Pierre Dourlen; Julien Chapuis; Gernot Kleinberger; Marc Gistelinck; Christine Van Broeckhoven; Jean-Charles Lambert; Frank Hirth; Stein Aerts; Patrick Callaerts; Bart Dermaut

doi:10.1016/j.celrep.2012.12.014

TDP-43 Loss-of-Function Causes Neuronal Loss Due to Defective Steroid Receptor-Mediated Gene Program Switching in Drosophilia

Lies Vanden Broeck, Marina Naval-Sánchez, Yoshitsugu Adachi, Danielle Diaper, Pierre Dourlen, Julien Chapuis, Gernot Kleinberger, Marc Gistelinck, Christine Van Broeckhoven, Jean-Charles Lambert, Frank Hirth, Stein Aerts, Patrick Callaerts, Bart Dermaut

Basic and Clinical Neuroscience

Research output: Contribution to journal › Article › peer-review

50 Citations (Scopus)

Abstract

TDP-43 proteinopathy is strongly implicated in the pathogenesis of amyotrophic lateral sclerosis and related neurodegenerative disorders. Whether TDP-43 neurotoxicity is caused by a novel toxic gain-of-function mechanism of the aggregates or by a loss of its normal function is unknown. We increased and decreased expression of TDP-43 (dTDP-43) in Drosophila. Although upregulation of dTDP-43 induced neuronal ubiquitin and dTDP-43-positive inclusions, both up- and downregulated dTDP-43 resulted in selective apoptosis of bursicon neurons and highly similar transcriptome alterations at the pupal-adult transition. Gene network analysis and genetic validation showed that both up- and downregulated dTDP-43 directly and dramatically increased the expression of the neuronal microtubule-associated protein Map205, resulting in cytoplasmic accumulations of the ecdysteroid receptor (EcR) and a failure to switch EcR-dependent gene programs from a pupal to adult pattern. We propose that dTDP-43 neurotoxicity is caused by a loss of its normal function.

Original language	English
Pages (from-to)	160-172
Number of pages	13
Journal	Cell Reports
Volume	3
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2012.12.014
Publication status	Published - 31 Jan 2013

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Vanden Broeck, L., Naval-Sánchez, M., Adachi, Y., Diaper, D., Dourlen, P., Chapuis, J., Kleinberger, G., Gistelinck, M., Van Broeckhoven, C., Lambert, J.-C., Hirth, F., Aerts, S., Callaerts, P., & Dermaut, B. (2013). TDP-43 Loss-of-Function Causes Neuronal Loss Due to Defective Steroid Receptor-Mediated Gene Program Switching in Drosophilia. Cell Reports, 3(1), 160-172. https://doi.org/10.1016/j.celrep.2012.12.014

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title = "TDP-43 Loss-of-Function Causes Neuronal Loss Due to Defective Steroid Receptor-Mediated Gene Program Switching in Drosophilia",

abstract = "TDP-43 proteinopathy is strongly implicated in the pathogenesis of amyotrophic lateral sclerosis and related neurodegenerative disorders. Whether TDP-43 neurotoxicity is caused by a novel toxic gain-of-function mechanism of the aggregates or by a loss of its normal function is unknown. We increased and decreased expression of TDP-43 (dTDP-43) in Drosophila. Although upregulation of dTDP-43 induced neuronal ubiquitin and dTDP-43-positive inclusions, both up- and downregulated dTDP-43 resulted in selective apoptosis of bursicon neurons and highly similar transcriptome alterations at the pupal-adult transition. Gene network analysis and genetic validation showed that both up- and downregulated dTDP-43 directly and dramatically increased the expression of the neuronal microtubule-associated protein Map205, resulting in cytoplasmic accumulations of the ecdysteroid receptor (EcR) and a failure to switch EcR-dependent gene programs from a pupal to adult pattern. We propose that dTDP-43 neurotoxicity is caused by a loss of its normal function.",

author = "{Vanden Broeck}, Lies and Marina Naval-S{\'a}nchez and Yoshitsugu Adachi and Danielle Diaper and Pierre Dourlen and Julien Chapuis and Gernot Kleinberger and Marc Gistelinck and {Van Broeckhoven}, Christine and Jean-Charles Lambert and Frank Hirth and Stein Aerts and Patrick Callaerts and Bart Dermaut",

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doi = "10.1016/j.celrep.2012.12.014",

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Vanden Broeck, L, Naval-Sánchez, M, Adachi, Y , Diaper, D, Dourlen, P, Chapuis, J, Kleinberger, G, Gistelinck, M, Van Broeckhoven, C, Lambert, J-C, Hirth, F, Aerts, S, Callaerts, P & Dermaut, B 2013, 'TDP-43 Loss-of-Function Causes Neuronal Loss Due to Defective Steroid Receptor-Mediated Gene Program Switching in Drosophilia', Cell Reports, vol. 3, no. 1, pp. 160-172. https://doi.org/10.1016/j.celrep.2012.12.014

TY - JOUR

T1 - TDP-43 Loss-of-Function Causes Neuronal Loss Due to Defective Steroid Receptor-Mediated Gene Program Switching in Drosophilia

AU - Vanden Broeck, Lies

AU - Naval-Sánchez, Marina

AU - Adachi, Yoshitsugu

AU - Diaper, Danielle

AU - Dourlen, Pierre

AU - Chapuis, Julien

AU - Kleinberger, Gernot

AU - Gistelinck, Marc

AU - Van Broeckhoven, Christine

AU - Lambert, Jean-Charles

AU - Hirth, Frank

AU - Aerts, Stein

AU - Callaerts, Patrick

AU - Dermaut, Bart

PY - 2013/1/31

Y1 - 2013/1/31

N2 - TDP-43 proteinopathy is strongly implicated in the pathogenesis of amyotrophic lateral sclerosis and related neurodegenerative disorders. Whether TDP-43 neurotoxicity is caused by a novel toxic gain-of-function mechanism of the aggregates or by a loss of its normal function is unknown. We increased and decreased expression of TDP-43 (dTDP-43) in Drosophila. Although upregulation of dTDP-43 induced neuronal ubiquitin and dTDP-43-positive inclusions, both up- and downregulated dTDP-43 resulted in selective apoptosis of bursicon neurons and highly similar transcriptome alterations at the pupal-adult transition. Gene network analysis and genetic validation showed that both up- and downregulated dTDP-43 directly and dramatically increased the expression of the neuronal microtubule-associated protein Map205, resulting in cytoplasmic accumulations of the ecdysteroid receptor (EcR) and a failure to switch EcR-dependent gene programs from a pupal to adult pattern. We propose that dTDP-43 neurotoxicity is caused by a loss of its normal function.

AB - TDP-43 proteinopathy is strongly implicated in the pathogenesis of amyotrophic lateral sclerosis and related neurodegenerative disorders. Whether TDP-43 neurotoxicity is caused by a novel toxic gain-of-function mechanism of the aggregates or by a loss of its normal function is unknown. We increased and decreased expression of TDP-43 (dTDP-43) in Drosophila. Although upregulation of dTDP-43 induced neuronal ubiquitin and dTDP-43-positive inclusions, both up- and downregulated dTDP-43 resulted in selective apoptosis of bursicon neurons and highly similar transcriptome alterations at the pupal-adult transition. Gene network analysis and genetic validation showed that both up- and downregulated dTDP-43 directly and dramatically increased the expression of the neuronal microtubule-associated protein Map205, resulting in cytoplasmic accumulations of the ecdysteroid receptor (EcR) and a failure to switch EcR-dependent gene programs from a pupal to adult pattern. We propose that dTDP-43 neurotoxicity is caused by a loss of its normal function.

U2 - 10.1016/j.celrep.2012.12.014

DO - 10.1016/j.celrep.2012.12.014

M3 - Article

C2 - 23333275

SN - 2211-1247

VL - 3

SP - 160

EP - 172

JO - Cell Reports

JF - Cell Reports

IS - 1

ER -

TDP-43 Loss-of-Function Causes Neuronal Loss Due to Defective Steroid Receptor-Mediated Gene Program Switching in Drosophilia

Abstract

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