Restoration of motor defects caused by loss of drosophila TDP-43 by expression of the voltage-gated calcium channel, cacophony, in central neurons

Kayly M. Lembke, Charles Scudder, David Morton

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Defects in the RNA-binding protein, TDP-43, are known to cause a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal lobar dementia. A variety of experimental systems have shown that neurons are sensitive to TDP-43 expression levels, yet the specific functional defects resulting from TDP-43 dysregulation have not been well described. Using the Drosophila TDP-43 ortholog TBPH, we previously showed that TBPH-null animals display locomotion defects as third instar larvae. Furthermore, loss of TBPH caused a reduction in cacophony, a Type II voltage-gated calcium channel, expression and that genetically restoring cacophony in motor neurons in TBPH mutant animals was sufficient to rescue the locomotion defects. In the present study, we examined the relative contributions of neuromuscular junction physiology and the motor program to the locomotion defects and identified subsets of neurons that require cacophony expression to rescue the defects. At the neuromuscular junction, we showed mEPP amplitudes and frequency require TBPH. Cacophony expression in motor neurons rescuedmEPPfrequency but notmEPPamplitude.We also showed that TBPH mutants displayed reduced motor neuron bursting and coordination during crawling and restoring cacophony selectively in two pairs of cells located in the brain, the AVM001b/2b neurons, also rescued the locomotion and motor defects, but not the defects in neuromuscular junction physiology. These results suggest that the behavioral defects associated with loss of TBPH throughout the nervous system can be associated with defects in a small number of genes in a limited number of central neurons, rather than peripheral defects.

Original languageEnglish (US)
Pages (from-to)9486-9497
Number of pages12
JournalJournal of Neuroscience
Volume37
Issue number39
DOIs
StatePublished - Sep 27 2017

Keywords

  • Amyotrophic lateral sclerosis
  • Calcium channel
  • Frontotemporal lobar dementia
  • Motor program
  • TDP-43

ASJC Scopus subject areas

  • Neuroscience(all)

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