Trends in Neurosciences
Research Focus‘Unfolding’ pathways in neurodegenerative disease
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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Cited by (167)
Lysosomal functions and dysfunctions: Molecular and cellular mechanisms underlying Gaucher disease and its association with Parkinson disease
2022, Advanced Drug Delivery ReviewsCitation Excerpt :It is well known that dopaminergic neurons produce and consume a great amount of ATP due to the millions of synapse connections they form, and, therefore, a decline in energy production affects their function [132–135]. Accumulation of misfolded proteins and ER stress were implicated in PD [157–160]. In a very comprehensive study [161] the authors generated cortical neurons from induced pluripotent stem cells (iPSCs) of patients harboring α-synuclein mutations, who are at high risk of developing PD.
The unfolded protein response and apoptotic regulation in the human placenta due to maternal cigarette smoking and pre-eclampsia
2021, Reproductive ToxicologyCitation Excerpt :The unfolded protein response (UPR) deals with the accumulation of misfolded proteins in cells [1].
Exploring ER stress response in cellular aging and neuroinflammation in Alzheimer's disease
2021, Ageing Research ReviewsCitation Excerpt :The pathogenesis of neurodegenerative diseases are not very clearly defined. However, it is well understood that ER stress and UPR activation result in the formation and accumulation of abnormal proteins, leading to age-related neurodegeneration (Forman et al., 2003; Joshi and Johnson, 2012; Xiang et al., 2017). Neurodegenerative diseases such as AD, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease (Hou et al., 2019) are mostly diseases of old age and occur later in life (Gammon, 2014; Wyss-Coray, 2016).
Pathogenic tau does not drive activation of the unfolded protein response
2019, Journal of Biological Chemistry