title: Cellular abnormalities linked to endoplasmic reticulum dysfunction in cerebrovascular disease--therapeutic potential.
abstract: Unfolded proteins accumulate in the lumen of the endoplasmic reticulum (ER) as part of the cellular response to cerebral hypoxia/ischemia and also to the overexpression of the mutant genes responsible for familial forms of degenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyothrophic lateral sclerosis, and Huntington's disease, as well as other disorders that are caused by an expanded CAG repeat. This accumulation arises from an imbalance between the load of proteins that need to be folded and processed in the ER lumen and the ER folding/processing capacity. To withstand such potentially lethal conditions, stress responses are activated that includes the shutdown of translation to reduce the ER work load and the activation of the expression of genes coding for proteins involved in the folding and processing reactions, to increase folding/processing capacity. In transient cerebral ischemia, ER stress-induced suppression of protein synthesis is believed to be too severe to permit sufficient activation of the genetic arm of the ER stress response. Mutations associated with Alzheimer's disease down-regulate the ER stress response and make cells more vulnerable to conditions associated with ER stress. When the functioning of the ER is severely impaired and affected cells can no longer withstand these stressful conditions, programmed cell death is induced, including a mitochondria-driven apoptotic pathway. Raising the resistance of cells to conditions that interfere with ER functions and activating the degradation and refolding of unfolded proteins accumulated in the ER lumen are possible strategies for blocking the pathological process leading to cell death at an early stage.
authors.affiliation: Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center, Department of Anesthesiology, 132 Sands Building, Research Drive, Durham, NC 27710, USA. wulf.paschen@duke.edu
authors.forename: Wulf
authors.initials: W
authors.lastname: Paschen
authors.forename: Thorsten
authors.initials: T
authors.lastname: Mengesdorf
mesh_terms: D000818:Animals; D017209:Apoptosis; D002561:Cerebrovascular Disorders / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D006801:Humans; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D018696:Neuroprotective Agents; D017510:Protein Folding
chemical_list: D018696:Neuroprotective Agents