Trends in Neurosciences
Volume 26, Issue 8, August 2003, Pages 407-410
Journal home page for Trends in Neurosciences

Research Focus
‘Unfolding’ pathways in neurodegenerative disease

https://doi.org/10.1016/S0166-2236(03)00197-8Get rights and content

Abstract

The endoplasmic reticulum responds to stress by initiating a cascade of events known as the ‘unfolded-protein response’ (UPR). The accumulation of misfolded proteins in the leukodystrophy Pelizaeus-Merzbacher disease activates this stress response, resulting in apoptosis of oligodendrocytes. Although it remains uncertain whether the UPR plays a mechanistic role in prototypical neurodegenerative disorders such as Alzheimer's disease, this is plausible because misfolded proteins are directly implicated in the pathogenesis of these disorders.

Section snippets

The unfolded-protein response

Eukaryotic organisms have evolved specific signaling pathways to ensure that the protein-folding capacity of the ER is not overwhelmed. Upon accumulation of unfolded proteins the UPR is activated, leading to increased transcription of a characteristic set of genes and to reduced general protein translation. These adaptations have the net effect of reducing the amount of new protein translocated into the ER, increasing degradation of misfolded proteins and enhancing the protein-folding capacity

The UPR and neurodegenerative disease

In addition to Pelizaeus-Merzbacher disease (PMD), the UPR could be involved in the pathogenesis of several neurodegenerative disorders (Fig. 1). In Alzheimer's disease, presenilin 1, the putative γ-secretase necessary for generating Aβ, might be required for the activation and nuclear localization of IRE1 [8], and BiP binds the amyloid precursor protein (APP) in healthy cells, thereby limiting production of Aβ [9]. Moreover, mutations in presenilin 1 associated with familial Alzheimer's

Concluding remarks

In neurodegenerative disorders, the connection between the accumulation of misfolded protein aggregates and disease phenotype is incomplete. In many instances, the accumulation of these abnormal proteins is cytotoxic, owing to the intrinsic deleterious effects of the misfolded disease proteins themselves, the amyloid aggregates they form, or both. However, the direct or indirect activation of the UPR could represent an ‘unfolding’ pathway in disease pathogenesis. Further insights into these

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