| RRC ID |
84040
|
| 著者 |
Waldherr SM, Han M, Saxton AD, Vadset TA, McMillan PJ, Wheeler JM, Liachko NF, Kraemer BC.
|
| タイトル |
Endoplasmic reticulum unfolded protein response transcriptional targets of XBP-1s mediate rescue from tauopathy.
|
| ジャーナル |
Commun Biol
|
| Abstract |
Pathological tau disrupts protein homeostasis (proteostasis) within neurons in Alzheimer's disease (AD) and related disorders. We previously showed constitutive activation of the endoplasmic reticulum unfolded protein response (UPRER) transcription factor XBP-1s rescues tauopathy-related proteostatic disruption in a tau transgenic Caenorhabditis elegans (C. elegans) model of human tauopathy. XBP-1s promotes clearance of pathological tau, and loss of function of the ATF-6 branch of the UPRER prevents XBP-1s rescue of tauopathy in C. elegans. We conducted transcriptomic analysis of tau transgenic and xbp-1s transgenic C. elegans and found 116 putative target genes significantly upregulated by constitutively active XBP-1s. Among these were five candidate XBP-1s target genes with human orthologs and a previously known association with ATF6 (csp-1, dnj-28, hsp-4, ckb-2, and lipl-3). We examined the functional involvement of these targets in XBP-1s-mediated tauopathy suppression and found loss of function in any one of these genes completely disrupts XBP-1s suppression of tauopathy. Further, we demonstrate upregulation of HSP-4, C. elegans BiP, partially rescues tauopathy independent of other changes in the transcriptional network. Understanding how the UPRER modulates pathological tau accumulation will inform neurodegenerative disease mechanisms and direct further study in mammalian systems with the long-term goal of identifying therapeutic targets in human tauopathies.
|
| 巻・号 |
7(1)
|
| ページ |
903
|
| 公開日 |
2024-7-25
|
| DOI |
10.1038/s42003-024-06570-2
|
| PII |
10.1038/s42003-024-06570-2
|
| PMID |
39060347
|
| PMC |
PMC11282107
|
| MeSH |
Animals
Animals, Genetically Modified*
Caenorhabditis elegans* / genetics
Caenorhabditis elegans* / metabolism
Caenorhabditis elegans Proteins* / genetics
Caenorhabditis elegans Proteins* / metabolism
Carrier Proteins
Disease Models, Animal
Endoplasmic Reticulum / genetics
Endoplasmic Reticulum / metabolism
Gene Expression Regulation
Humans
Tauopathies* / genetics
Tauopathies* / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism
Unfolded Protein Response*
X-Box Binding Protein 1 / genetics
X-Box Binding Protein 1 / metabolism
tau Proteins / genetics
tau Proteins / metabolism
|
| リソース情報 |
| 線虫 |
tm5587
tm6492
tm6913 |
