Premium
XBP 1 depletion precedes ubiquitin aggregation and Golgi fragmentation in TDP ‐43 transgenic rats
Author(s) -
Tong Jianbin,
Huang Cao,
Bi Fangfang,
Wu Qinxue,
Huang Bo,
Zhou Hongxia
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12014
Subject(s) - endoplasmic reticulum , unfolded protein response , microbiology and biotechnology , golgi apparatus , endoplasmic reticulum associated protein degradation , ubiquitin , mutant , protein aggregation , biology , inclusion bodies , neurodegeneration , chemistry , biochemistry , gene , medicine , disease , escherichia coli , pathology
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 ( XBP 1), 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.