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High-throughput Screening for Protein-based Inheritance in S. cerevisiae
Published on: August 8, 2017
Unfolded protein response transcription factor XBP-1 does not influence prion replication or pathogenesis
Claudio Hetz1, Ann-Hwee Lee, Dennisse Gonzalez-Romero
1Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA. chetz@med.uchile.cl
Summary
The unfolded protein response (UPR) pathway, regulated by X-box-binding protein-1 (XBP-1), does not impact prion disease progression or neurodegeneration. This suggests XBP-1
Area of Science:
- Neuroscience
- Molecular Biology
- Cellular Biology
Background:
- The unfolded protein response (UPR) is a cellular stress response crucial for maintaining endoplasmic reticulum (ER) homeostasis.
- X-box-binding protein-1 (XBP-1) is a central regulator of the UPR, orchestrating adaptive gene expression to resolve ER stress.
- Chronic ER stress and protein misfolding are implicated in neurodegenerative diseases, but the UPR's role in the central nervous system (CNS) remains unclear.
Purpose of the Study:
- To investigate the role of XBP-1 in the CNS under conditions of ER stress and neurodegeneration.
- To determine if XBP-1 deficiency affects prion disease pathogenesis.
- To assess the contribution of the UPR to neuroprotection in prion-induced neurodegeneration.
Main Methods:
- Generation of a brain-specific XBP-1 conditional knockout mouse model (XBP-1(Nes-/-)).
- Assessment of ER stress signaling in primary neuronal cultures from XBP-1(Nes-/-) mice.
- Infection of XBP-1(Nes-/-) mice with murine prions to model neurodegenerative disease.
- Evaluation of prion aggregation, neuronal loss, and survival rates in knockout and wild-type mice.
Main Results:
- XBP-1(Nes-/-) mice were viable and showed no spontaneous neurological deficits, despite impaired ER stress signaling in neuronal cultures.
- Prion replication in XBP-1(Nes-/-) mice did not alter stress response activation.
- Prion aggregation, neuronal loss, and survival were unaffected by the absence of XBP-1 in the brain.
Conclusions:
- The brain-specific UPR pathway mediated by XBP-1 does not play a significant role in the pathogenesis of prion-induced neurodegeneration.
- Despite theoretical links between ER stress and neurodegenerative diseases, the XBP-1 arm of the UPR is not essential for prion disease progression.
- These findings challenge the direct contribution of this conserved UPR pathway to neurodegenerative conditions characterized by protein misfolding.
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