title: Parkin ubiquitinates Tar-DNA binding protein-43 (TDP-43) and promotes its cytosolic accumulation via interaction with histone deacetylase 6 (HDAC6).
abstract: The importance of E3 ubiquitin ligases, involved in the degradation of misfolded proteins or promotion of protein-protein interaction, is increasingly recognized in neurodegeneration. TDP-43 is a predominantly nuclear protein, which regulates the transcription of thousands of genes and binds to mRNA of the E3 ubiquitin ligase Parkin to regulate its expression. Wild type and mutated TDP-43 are detected in ubiquitinated forms within the cytosol in several neurodegenerative diseases. We elucidated the mechanisms of TDP-43 interaction with Parkin using transgenic A315T mutant TDP-43 (TDP43-Tg) mice, lentiviral wild type TDP-43, and Parkin gene transfer rat models. TDP-43 expression increased Parkin mRNA and protein levels. Lentiviral TDP-43 increased the levels of nuclear and cytosolic protein, whereas Parkin co-expression mediated Lys-48 and Lys-63-linked ubiquitin to TDP-43 and led to cytosolic co-localization of Parkin with ubiquitinated TDP-43. Parkin and TDP-43 formed a multiprotein complex with HDAC6, perhaps to mediate TDP-43 translocation. In conclusion, Parkin ubiquitinates TDP-43 and facilitates its cytosolic accumulation through a multiprotein complex with HDAC6.
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, D. C. 20007, USA.
authors.forename: Michaeline L
authors.initials: ML
authors.lastname: Hebron
authors.forename: Irina
authors.initials: I
authors.lastname: Lonskaya
authors.forename: Kaydee
authors.initials: K
authors.lastname: Sharpe
authors.forename: Puwakdandawe P K
authors.initials: PP
authors.lastname: Weerasinghe
authors.forename: Norah K
authors.initials: NK
authors.lastname: Algarzae
authors.forename: Ashot R
authors.initials: AR
authors.lastname: Shekoyan
authors.forename: Charbel E-H
authors.initials: CE
authors.lastname: Moussa
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000235:genetics; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D004268:DNA-Binding Proteins; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D044767:Ubiquitin-Protein Ligases; C578077:Tardbp protein, mouse; C111567:parkin protein; C433811:HDAC6 protein, human; C545556:HDAC6 protein, rat; C499033:Hdac6 protein, mouse