title: XBP1 depletion precedes ubiquitin aggregation and Golgi fragmentation in TDP-43 transgenic rats.
abstract: Protein inclusion is a prominent feature of neurodegenerative diseases including frontotemporal lobar degeneration (FTLD) that is characterized by the presence of ubiquitinated TDP-43 inclusion. Presence of protein inclusions indicates an interruption to protein degradation machinery or the overload of misfolded proteins. In response to the increase in misfolded proteins, cells usually initiate a mechanism called unfolded protein response (UPR) to reduce misfolded proteins in the lumen of endoplasmic reticules. Here, we examined the effects of mutant TDP-43 on the UPR in transgenic rats that express mutant human TDP-43 restrictedly in the neurons of the forebrain. Over-expression of mutant TDP-43 in rats caused prominent aggregation of ubiquitin and remarkable fragmentation of Golgi complexes prior to neuronal loss. While ubiquitin aggregates and Golgi fragments were accumulating, neurons expressing mutant TDP-43 failed to up-regulate chaperones residing in the endoplasmic reticules and failed to initiate the UPR. Prior to ubiquitin aggregation and Golgi fragmentation, neurons were depleted of X-box-binding protein 1 (XBP1), a key player of UPR machinery. Although it remains to determine how mutation of TDP-43 leads to the failure of the UPR, our data demonstrate that failure of the UPR is implicated in TDP-43 pathogenesis.
authors.affiliation: Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Tong
authors.forename: Cao
authors.initials: C
authors.lastname: Huang
authors.forename: Fangfang
authors.initials: F
authors.lastname: Bi
authors.forename: Qinxue
authors.initials: Q
authors.lastname: Wu
authors.forename: Bo
authors.initials: B
authors.lastname: Huang
authors.forename: Hongxia
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000367:Age Factors; D000818:Animals; D016923:Cell Death / Q000502:physiology; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics*; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D016548:Prosencephalon / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D000071701:Regulatory Factor X Transcription Factors; D057177:TDP-43 Proteinopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000502:physiology; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D025801:Ubiquitin; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605545:Xbp1 protein, rat