TDP-43 proteinopathy in Theiler’s murine encephalomyelitis virus infection

Katsuhisa Masaki, Yoshifumi Sonobe, Ghanashyam Ghadge, Peter Pytel, Raymond P. Roos

Research output: Contribution to journalArticle

Abstract

TDP-43, an RNA-binding protein that is primarily nuclear and important in splicing and RNA metabolism, is mislocalized from the nucleus to the cytoplasm of neural cells in amyotrophic lateral sclerosis (ALS), and contributes to disease. We sought to investigate whether TDP-43 is mislocalized in infections with the acute neuronal GDVII strain and the persistent demyelinating DA strain of Theiler’s virus murine encephalomyelitis virus (TMEV), a member of the Cardiovirus genus of Picornaviridae because: i) L protein of both strains is known to disrupt nucleocytoplasmic transport, including transport of polypyrimidine tract binding protein, an RNA-binding protein, ii) motor neurons and oligodendrocytes are targeted in both TMEV infection and ALS. TDP-43 phosphorylation, cleavage, and cytoplasmic mislocalization to an aggresome were observed in wild type TMEV-infected cultured cells, with predicted splicing abnormalities. In contrast, cells infected with DA and GDVII strains that have L deletion had rare TDP-43 mislocalization and no aggresome formation. TDP-43 mislocalization was also present in neural cells of TMEV acutely-infected mice. Of note, TDP-43 was mislocalized six weeks after DA infection to the cytoplasm of oligodendrocytes and other glial cells in demyelinating lesions of spinal white matter. A recent study showed that TDP-43 knock down in oligodendrocytes in mice led to demyelination and death of this neural cell [1], suggesting that TMEV infection mislocalization of TDP-43 and other RNA-binding proteins is predicted to disrupt key cellular processes and contribute to the pathogenesis of TMEV-induced diseases. Drugs that inhibit nuclear export may have a role in antiviral therapy.

Original languageEnglish
Article numbere1007574
JournalPLoS pathogens
Volume15
Issue number2
DOIs
Publication statusPublished - Feb 1 2019

Fingerprint

Maus Elberfeld virus
TDP-43 Proteinopathies
Theilovirus
Virus Diseases
RNA-Binding Proteins
Oligodendroglia
Cell Nucleus Active Transport
Amyotrophic Lateral Sclerosis
Cardiovirus
Cytoplasm
Polypyrimidine Tract-Binding Protein
Picornaviridae
RNA Splicing
Motor Neurons
Demyelinating Diseases
Infection
Protein Binding
Neuroglia
Antiviral Agents
Cultured Cells

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

TDP-43 proteinopathy in Theiler’s murine encephalomyelitis virus infection. / Masaki, Katsuhisa; Sonobe, Yoshifumi; Ghadge, Ghanashyam; Pytel, Peter; Roos, Raymond P.

In: PLoS pathogens, Vol. 15, No. 2, e1007574, 01.02.2019.

Research output: Contribution to journalArticle

Masaki, Katsuhisa ; Sonobe, Yoshifumi ; Ghadge, Ghanashyam ; Pytel, Peter ; Roos, Raymond P. / TDP-43 proteinopathy in Theiler’s murine encephalomyelitis virus infection. In: PLoS pathogens. 2019 ; Vol. 15, No. 2.
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