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Endoplasmic Reticulum Protein Quality Control in Neurodegenerative Disease: The Good, the Bad and the Therapy

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Abstract:

Neurodegenerative disorders are often characterized by the aggregation and accumulation of misfolded proteins (e.g. Alzheimer's disease, Parkinson’s disease, Amyotrophic lateral sclerosis). Aggregated proteins are very toxic to cells in culture and both in vitro and in vivo there is overwhelming evidence that these aberrant proteins are key players in neurodegeneration. Protein quality control is a cellular defense mechanism against misfolded proteins that prevents aggregate formation under physiological conditions. The presence of accumulated aggregates of misfolded proteins in many neurodegenerative disorders, suggests that protein quality control failed to restore homeostasis in these pathological conditions. In fact, evidence from observations in cellular disease models, mouse models, as well as from post mortem patient material indicates activation of the quality control machinery in response to the pathological process. In addition, interference with protein quality control by genetic or chemical manipulation often results in aggregate formation and neurodegeneration. This stresses the importance of proper quality control in neurodegenerative disorders and indicates that it may provide a target for therapeutic intervention. In this review we will focus on the protein quality control systems in the endoplasmic reticulum (ER) and address the involvement of ER quality control in neurodegenerative disease as well as its potential as therapeutic target.

Keywords: Alzheimer's disease; Amyotrophic lateral sclerosis; ER stress; ERAD; Parkinson's disease; autophagy; endoplasmic reticulum; neurodegeneration; proteasome; protein quality control

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986709787458506

Affiliations: Academic Medical Center, Neurogenetics Laboratory, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands.

Publication date: February 1, 2009

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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