Open AccessSplicing repression is a major function of TDP-43 in motor neurons
Author(s) -
Aneesh Donde,
Mingkuan Sun,
Jonathan P. Ling,
Kerstin E. Braunstein,
Bo Pang,
Xinrui Wen,
Xiao Cheng,
Liam Chen,
Philip C. Wong
Publication year - 2019
Publication title -
acta neuropathologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.183
H-Index - 170
eISSN - 1432-0533
pISSN - 0001-6322
DOI - 10.1007/s00401-019-02042-8
Subject(s) - rna splicing , biology , neurodegeneration , motor neuron , amyotrophic lateral sclerosis , alternative splicing , neuroscience , repressor , rna binding protein , psychological repression , microbiology and biotechnology , rna , genetics , gene expression , gene , messenger rna , spinal cord , medicine , disease
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.