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'Unfolding' pathways in neurodegenerative disease
Mark S Forman1, Virginia M-Y Lee, John Q Trojanowski
1Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 3600 Spruce Street, Maloney Building, 3rd Floor, Philadelphia, PA 19104, USA. formanm@mail.med.upenn.edu
Trends in Neurosciences
|August 6, 2003
Summary
The unfolded-protein response (UPR) is activated by misfolded proteins, causing oligodendrocyte cell death in Pelizaeus-Merzbacher disease. This stress pathway may also contribute to neurodegenerative disorders like Alzheimer's disease.
Area of Science:
- Cellular stress response pathways
- Neurodegenerative disease mechanisms
- Protein folding and misfolding
Background:
- The endoplasmic reticulum (ER) initiates the unfolded-protein response (UPR) to manage cellular stress.
- Misfolded proteins accumulate in Pelizaeus-Merzbacher disease, triggering the UPR.
- Oligodendrocyte apoptosis is a consequence of UPR activation in this leukodystrophy.
Purpose of the Study:
- To investigate the role of the unfolded-protein response (UPR) in Pelizaeus-Merzbacher disease.
- To explore the potential involvement of the UPR in other neurodegenerative disorders, such as Alzheimer's disease.
Main Methods:
- Analysis of the unfolded-protein response (UPR) activation in Pelizaeus-Merzbacher disease models.
- Examination of oligodendrocyte apoptosis pathways.
- Correlation of misfolded protein accumulation with UPR markers.
Main Results:
- Accumulation of misfolded proteins in Pelizaeus-Merzbacher disease leads to UPR activation.
- UPR activation results in apoptosis of oligodendrocytes.
- The UPR's role in Alzheimer's disease pathogenesis is plausible due to implicated misfolded proteins.
Conclusions:
- The unfolded-protein response (UPR) is implicated in Pelizaeus-Merzbacher disease pathogenesis through oligodendrocyte apoptosis.
- The UPR represents a potential therapeutic target for neurodegenerative diseases involving protein misfolding.