Article

TDP-43 Phosphorylation by Casein Kinase I{epsilon} Promotes Oligomerization and Enhances Toxicity In Vivo.

Department of Neuroscience and Cell Biology.
Human Molecular Genetics (Impact Factor: 6.68). 10/2013; 23(4). DOI: 10.1093/hmg/ddt498
Source: PubMed

ABSTRACT Dominant mutations in TDP-43 cause amyotrophic lateral sclerosis. TDP-43 inclusions occur in neurons, glia, and muscle in this disease and in sporadic and inherited forms of frontotemporal lobar degeneration. Cytoplasmic localization, cleavage, aggregation, and phosphorylation of TDP-43 at the Ser409/410 epitope have been associated with disease pathogenesis. TDP-43 aggregation is not a common feature of mouse models of TDP-43 proteinopathy, and TDP-43 is generally not thought to acquire an amyloid conformation or form fibrils. A number of putative TDP-43 kinases have been identified, but whether any of these function to regulate TDP-43 phosphorylation or toxicity in vivo is not known. Here, we demonstrate that human TDP-43(Q331 K) undergoes cytoplasmic localization and aggregates when misexpressed in Drosophila as compared to wild type and M337 V forms. Co expression of Q331 K with doubletime (DBT), the fly homolog of casein kinase Iε (CKIε), enhances toxicity. There is at best modest basal phosphorylation of misexpressed human TDP-43 in Drosophila, but coexpression with DBT increases Ser409/410 phosphorylation of all TDP-43 isoforms tested. Phosphorylation of TDP-43 in the fly is specific for DBT, as it is not observed using the validated tau kinases GSK-3β, PAR-1/MARK2, or CDK5. Co expression of DBT with TDP-43(Q331 K) enhances the formation of high molecular weight oligomeric species coincident with enhanced toxicity, and treatment of recombinant oligomeric TDP-43 with rat CKI strongly enhances its toxicity in mammalian cell culture. These data identify CKIε as a potent TDP-43 kinase in vivo and implicate oligomeric species as the toxic entities in TDP-43 proteinopathies.

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