. Differential effects of unfolded protein response pathways on axon injury-induced death of retinal ganglion cells. Neuron. 2012 Feb 9;73(3):445-52. PubMed.

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  1. In this paper, Hu and colleagues explore the role of the unfolded protein response (UPR) in neurodegeneration of retinal ganglion cells in the context of traumatic optic nerve injury and glaucoma. The data presented may indicate that selective activation of one of the three UPR signaling pathways may occur in neurons.

    The authors raise the interesting idea that the morphological structure of the neuron contributes to a specific regulation of the UPR that differs from other cell types. The signaling cascade initiated by the UPR might be different in the axons compared to that in the soma of the neuron. This is an interesting aspect; however, this requires further investigation using more specific UPR activation markers because non-UPR signaling pathways converge with the UPR on the downstream targets analyzed in this study.

    Hu et al. show that differential modulation of targets located in different signaling cascades of the UPR stimulates neuronal survival. In their models, they show that deletion of CHOP and increased expression of XBP-1 improve neuronal survival. However, in the current study, no link was observed between these effects and the activation of regenerative pathways. Somehow this makes sense, because during endoplasmic reticulum (ER) stress a cell’s first priority would be restoration of ER homeostasis before embarking on cell division and other regenerative processes. Activation of the UPR in neuroblastoma cells induces a cell cycle arrest, and in AD the UPR activation markers negatively correlate with the expression of cell cycle proteins, which potentially have a regenerative function in early AD (1). Signaling cascades of the UPR that actively block a regenerative process could play an important role in neurodegenerative diseases, and need to be addressed in future studies.

    In neurodegenerative diseases like Alzheimer’s disease (AD), frontotemporal dementia (FTD), and Parkinson’s disease, UPR activation is observed in neurons in close association with the accumulation of misfolded proteins that occurs in these diseases (2-4). In contrast to the observations in the traumatic optic nerve injury models, the available data support activation of all signaling pathways of the UPR in neurodegenerative diseases. Although the UPR is initially protective, it is suggested that its prolonged activation contributes to the neurodegenerative process. However, the outcome of UPR activation due to acute and chronic stress appears different. For instance, UPR activation after traumatic optic nerve injury contributes to neuronal loss via apoptosis, while there is substantial evidence that in AD and FTD, the UPR is involved in the phosphorylation and accumulation of the microtubule-associated protein, tau. The involvement of the UPR in these different diseases suggests that the UPR could be addressed as a therapeutic target to reduce neurodegenerative processes in general. Therefore, more insight should be gained in how the different signaling cascades of the UPR contribute to neurodegeneration. A part of this issue is nicely addressed by Hu and colleagues in the current paper.

    References:

    . The unfolded protein response affects neuronal cell cycle protein expression: implications for Alzheimer's disease pathogenesis. Exp Gerontol. 2006 Apr;41(4):380-6. PubMed.

    . Activation of the unfolded protein response in Parkinson's disease. Biochem Biophys Res Commun. 2007 Mar 16;354(3):707-11. PubMed.

    . The unfolded protein response is activated in pretangle neurons in Alzheimer's disease hippocampus. Am J Pathol. 2009 Apr;174(4):1241-51. PubMed.

    . The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies. J Pathol. 2011 Nov 21; PubMed.

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