title: TDP-43 regulates endogenous retrovirus-K viral protein accumulation.
abstract: The concomitant expression of neuronal TAR DNA binding protein 43 (TDP-43) and human endogenous retrovirus-K (ERVK) is a hallmark of ALS. Since the involvement of TDP-43 in retrovirus replication remains controversial, we sought to evaluate whether TDP-43 exerts an effect on ERVK expression. In this study, TDP-43 bound the ERVK promoter in the context of inflammation or proteasome inhibition, with no effect on ERVK transcription. However, over-expression of ALS-associated aggregating forms of TDP-43, but not wild-type TDP-43, significantly enhanced ERVK viral protein accumulation. Human astrocytes and neurons further demonstrated cell-type specific differences in their ability to express and clear ERVK proteins during inflammation and proteasome inhibition. Astrocytes, but not neurons, were able to clear excess ERVK proteins through stress granule formation and autophagy. In vitro findings were validated in autopsy motor cortex tissue from patients with ALS and neuro-normal controls. We further confirmed marked enhancement of ERVK in cortical neurons of patients with ALS. Despite evidence of enhanced stress granule and autophagic response in ALS cortical neurons, these cells failed to clear excess ERVK protein accumulation. This highlights how multiple cellular pathways, in conjunction with disease-associated mutations, can converge to modulate the expression and clearance of viral gene products from genomic elements such as ERVK. In ALS, ERVK protein aggregation is a novel aspect of TDP-43 misregulation contributing towards the pathology of this neurodegenerative disease.
authors.affiliation: Department of Biology, University of Winnipeg, 599 Portage Avenue, Winnipeg, Manitoba R3B 2G3, Canada.
authors.forename: Mamneet
authors.initials: M
authors.lastname: Manghera
authors.affiliation: Department of Biology, University of Winnipeg, 599 Portage Avenue, Winnipeg, Manitoba R3B 2G3, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ferguson-Parry
authors.affiliation: Department of Biology, University of Winnipeg, 599 Portage Avenue, Winnipeg, Manitoba R3B 2G3, Canada; Department of Immunology, University of Manitoba, 750 McDermot Avenue, Winnipeg, Manitoba R3E 0T5, Canada. Electronic address: r.douville@uwinnipeg.ca.
authors.forename: Renée N
authors.initials: RN
authors.lastname: Douville
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D001253:Astrocytes / Q000378:metabolism / Q000821:virology; D001343:Autophagy / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020077:Endogenous Retroviruses / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000473:pathology / Q000821:virology*; D009154:Mutation / Q000235:genetics; D014764:Viral Proteins / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human; D014764:Viral Proteins
keywords: Amyotrophic lateral sclerosis (ALS); Autophagy; Endogenous retrovirus (ERVK); Stress granule; TAR DNA-binding protein 43 (TDP-43)