Motor neurons and glia exhibit specific individualized responses to TDP-43 expression in a Drosophila model of amyotrophic lateral sclerosis

Patricia S. Estes, Scott G. Daniel, Abigail P. Mccallum, Ashley V. Boehringer, Alona S. Sukhina, Rebecca A. Zwick, Daniela C Zarnescu

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by complex neuronal and glial phenotypes. Recently, RNA-based mechanisms have been linked to ALS via RNA-binding proteins such as TDP-43, which has been studied in vivo using models ranging from yeast to rodents. We have developed a Drosophila model of ALS based on TDP-43 that recapitulates several aspects of pathology, including motor neuron loss, locomotor dysfunction and reduced survival. Here we report the phenotypic consequences of expressing wild-type and four different ALS-linked TDP-43 mutations in neurons and glia. We show that TDP-43-driven neurodegeneration phenotypes are dose- and age-dependent. In motor neurons, TDP-43 appears restricted to nuclei, which are significantly misshapen due to mutant but not wild-type protein expression. In glia and in the developing neuroepithelium, TDP-43 associates with cytoplasmic puncta. TDP-43-containing RNA granules are motile in cultured motor neurons, although wildtype and mutant variants exhibit different kinetic properties. At the neuromuscular junction, the expression of TDP-43 in motor neurons versus glia leads to seemingly opposite synaptic phenotypes that, surprisingly, translate into comparable locomotor defects. Finally, we explore sleep as a behavioral readout of TDP-43 expression and find evidence of sleep fragmentation consistent with hyperexcitability, a suggested mechanism in ALS. These findings support the notion that although motor neurons and glia are both involved in ALS pathology, at the cellular level they can exhibit different responses to TDP-43. In addition, our data suggest that individual TDP-43 alleles utilize distinct molecular mechanisms, which will be important for developing therapeutic strategies.

Original languageEnglish (US)
Pages (from-to)721-733
Number of pages13
JournalDMM Disease Models and Mechanisms
Volume6
Issue number3
DOIs
StatePublished - May 2013

Fingerprint

Amyotrophic Lateral Sclerosis
Motor Neurons
Neuroglia
Drosophila
Neurons
Pathology
Phenotype
RNA
Sleep Deprivation
RNA-Binding Proteins
Neuromuscular Junction
Yeast
Rodentia
Sleep
Yeasts
Alleles
Defects
Mutation
Kinetics
Proteins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Neuroscience (miscellaneous)

Cite this

Motor neurons and glia exhibit specific individualized responses to TDP-43 expression in a Drosophila model of amyotrophic lateral sclerosis. / Estes, Patricia S.; Daniel, Scott G.; Mccallum, Abigail P.; Boehringer, Ashley V.; Sukhina, Alona S.; Zwick, Rebecca A.; Zarnescu, Daniela C.

In: DMM Disease Models and Mechanisms, Vol. 6, No. 3, 05.2013, p. 721-733.

Research output: Contribution to journalArticle

Estes, Patricia S. ; Daniel, Scott G. ; Mccallum, Abigail P. ; Boehringer, Ashley V. ; Sukhina, Alona S. ; Zwick, Rebecca A. ; Zarnescu, Daniela C. / Motor neurons and glia exhibit specific individualized responses to TDP-43 expression in a Drosophila model of amyotrophic lateral sclerosis. In: DMM Disease Models and Mechanisms. 2013 ; Vol. 6, No. 3. pp. 721-733.
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