Abstract
Nuclear depletion of TDP-43, an essential RNA binding protein, may underlie neurodegeneration in amyotrophic lateral sclerosis (ALS). As several functions have been ascribed to this protein, the critical role(s) of TDP-43 in motor neurons that may be compromised in ALS remains unknown. We show here that TDP-43 mediated splicing repression, which serves to protect the transcriptome by preventing aberrant splicing, is central to the physiology of motor neurons. Expression in Drosophila TDP-43 knockout models of a chimeric repressor, comprised of the RNA recognition domain of TDP-43 fused to an unrelated splicing repressor, RAVER1, attenuated motor deficits and extended lifespan. Likewise, AAV9-mediated delivery of this chimeric rescue repressor to mice lacking TDP-43 in motor neurons delayed the onset, slowed the progression of motor symptoms, and markedly extended their lifespan. In treated mice lacking TDP-43 in motor neurons, aberrant splicing was significantly decreased and accompanied by amelioration of axon degeneration and motor neuron loss. This AAV9 strategy allowed long-term expression of the chimeric repressor without any adverse effects. Our findings establish that splicing repression is a major function of TDP-43 in motor neurons and strongly support the idea that loss of TDP-43-mediated splicing fidelity represents a key pathogenic mechanism underlying motor neuron loss in ALS.
| Original language | English (US) |
|---|---|
| Journal | Acta neuropathologica |
| DOIs | |
| State | Published - Jan 1 2019 |
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Keywords
- Amyotrophic lateral sclerosis
- Cryptic exon
- Drosophila
- Motor neuron
- Mouse
- TDP-43
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Clinical Neurology
- Cellular and Molecular Neuroscience
Cite this
Splicing repression is a major function of TDP-43 in motor neurons. / Donde, Aneesh; Sun, Mingkuan; Ling, Jonathan P.; Braunstein, Kerstin E.; Pang, Bo; Wen, Xinrui; Cheng, Xueying; Chen, Liam Lucian; Wong, Philip Chun.
In: Acta neuropathologica, 01.01.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Splicing repression is a major function of TDP-43 in motor neurons
AU - Donde, Aneesh
AU - Sun, Mingkuan
AU - Ling, Jonathan P.
AU - Braunstein, Kerstin E.
AU - Pang, Bo
AU - Wen, Xinrui
AU - Cheng, Xueying
AU - Chen, Liam Lucian
AU - Wong, Philip Chun
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Nuclear depletion of TDP-43, an essential RNA binding protein, may underlie neurodegeneration in amyotrophic lateral sclerosis (ALS). As several functions have been ascribed to this protein, the critical role(s) of TDP-43 in motor neurons that may be compromised in ALS remains unknown. We show here that TDP-43 mediated splicing repression, which serves to protect the transcriptome by preventing aberrant splicing, is central to the physiology of motor neurons. Expression in Drosophila TDP-43 knockout models of a chimeric repressor, comprised of the RNA recognition domain of TDP-43 fused to an unrelated splicing repressor, RAVER1, attenuated motor deficits and extended lifespan. Likewise, AAV9-mediated delivery of this chimeric rescue repressor to mice lacking TDP-43 in motor neurons delayed the onset, slowed the progression of motor symptoms, and markedly extended their lifespan. In treated mice lacking TDP-43 in motor neurons, aberrant splicing was significantly decreased and accompanied by amelioration of axon degeneration and motor neuron loss. This AAV9 strategy allowed long-term expression of the chimeric repressor without any adverse effects. Our findings establish that splicing repression is a major function of TDP-43 in motor neurons and strongly support the idea that loss of TDP-43-mediated splicing fidelity represents a key pathogenic mechanism underlying motor neuron loss in ALS.
AB - Nuclear depletion of TDP-43, an essential RNA binding protein, may underlie neurodegeneration in amyotrophic lateral sclerosis (ALS). As several functions have been ascribed to this protein, the critical role(s) of TDP-43 in motor neurons that may be compromised in ALS remains unknown. We show here that TDP-43 mediated splicing repression, which serves to protect the transcriptome by preventing aberrant splicing, is central to the physiology of motor neurons. Expression in Drosophila TDP-43 knockout models of a chimeric repressor, comprised of the RNA recognition domain of TDP-43 fused to an unrelated splicing repressor, RAVER1, attenuated motor deficits and extended lifespan. Likewise, AAV9-mediated delivery of this chimeric rescue repressor to mice lacking TDP-43 in motor neurons delayed the onset, slowed the progression of motor symptoms, and markedly extended their lifespan. In treated mice lacking TDP-43 in motor neurons, aberrant splicing was significantly decreased and accompanied by amelioration of axon degeneration and motor neuron loss. This AAV9 strategy allowed long-term expression of the chimeric repressor without any adverse effects. Our findings establish that splicing repression is a major function of TDP-43 in motor neurons and strongly support the idea that loss of TDP-43-mediated splicing fidelity represents a key pathogenic mechanism underlying motor neuron loss in ALS.
KW - Amyotrophic lateral sclerosis
KW - Cryptic exon
KW - Drosophila
KW - Motor neuron
KW - Mouse
KW - TDP-43
UR - http://www.scopus.com/inward/record.url?scp=85069482351&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85069482351&partnerID=8YFLogxK
U2 - 10.1007/s00401-019-02042-8
DO - 10.1007/s00401-019-02042-8
M3 - Article
C2 - 31332509
AN - SCOPUS:85069482351
JO - Acta Neuropathologica
JF - Acta Neuropathologica
SN - 0001-6322
ER -