XBP1 depletion precedes ubiquitin aggregation and Golgi fragmentation in TDP-43 transgenic rats

• Published in: Journal of neurochemistry Vol. 123; no. 3; pp. 406 - 416
• Main Authors: Tong, Jianbin, Huang, Cao, Bi, Fangfang, Wu, Qinxue, Huang, Bo, Zhou, Hongxia
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell Publishing Ltd 01.11.2012; Wiley-Blackwell
• Subjects: Age Factors; Animals; Biological and medical sciences; Cell Death - physiology; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dendrites - metabolism; Dendrites - pathology; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; Frontotemporal Lobar Degeneration - genetics; Frontotemporal Lobar Degeneration - metabolism; Frontotemporal Lobar Degeneration - pathology; Fundamental and applied biological sciences. Psychology; Golgi Apparatus - metabolism; Golgi fragmentation; Humans; Medical sciences; Memory Disorders - genetics; Memory Disorders - metabolism; Memory Disorders - pathology; Nerve Degeneration - genetics; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Neuroglia - metabolism; Neuroglia - pathology; Neurology; Neurons - metabolism; Neurons - pathology; Prosencephalon - cytology; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Regulatory Factor X Transcription Factors; TDP-43; TDP-43 Proteinopathies - genetics; TDP-43 Proteinopathies - metabolism; TDP-43 Proteinopathies - pathology; Transcription Factors - deficiency; Transcription Factors - genetics; Ubiquitin - metabolism; ubiquitin aggregation; Unfolded Protein Response - physiology; Vertebrates: nervous system and sense organs; X-Box Binding Protein 1; XBP1; Human; Ubiquitin; XBP1; Rat; Pathogenesis; Chaperone; Rodentia; Unfolded protein response; Aggregation; Binding protein; Vertebrata; Mammalia; Depletion; Golgi fragmentation; ubiquitin aggregation; TDP-43; Degeneration; Mutation; rats; Golgi neuron
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12014

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. Electromicroscopy reveals that ER is severely vacuolated in neurons while mitochondrial morphology is largely intact. ER likely is the preferable targets of degeneration caused by mutation in TDP‐43.