Article

Endoplasmic reticulum dysfunction in neurological disease

Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
The Lancet Neurology (Impact Factor: 21.9). 01/2013; 12(1):105-18. DOI: 10.1016/S1474-4422(12)70238-7
Source: PubMed

ABSTRACT

Endoplasmic reticulum (ER) dysfunction might have an important part to play in a range of neurological disorders, including cerebral ischaemia, sleep apnoea, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, the prion diseases, and familial encephalopathy with neuroserpin inclusion bodies. Protein misfolding in the ER initiates the well studied unfolded protein response in energy-starved neurons during stroke, which is relevant to the toxic effects of reperfusion. The toxic peptide amyloid β induces ER stress in Alzheimer's disease, which leads to activation of similar pathways, whereas the accumulation of polymeric neuroserpin in the neuronal ER triggers a poorly understood ER-overload response. In other neurological disorders, such as Parkinson's and Huntington's diseases, ER dysfunction is well recognised but the mechanisms by which it contributes to pathogenesis remain unclear. By targeting components of these signalling responses, amelioration of their toxic effects and so the treatment of a range of neurodegenerative disorders might become possible.

5 Followers
 · 
59 Reads
  • Source
    • "However, there is direct evidence that excessive or prolonged activation of ER stress can exacerbate ischemia injury. Particularly, the overactivation of the UPR may play a significant role in reperfusion, resulting in promoting cell death usually in the form of apoptosis (Roussel et al., 2013). It is known that reperfusion causes of excessive UPR, triggering depletion of ER Ca 2+ , abnormal aggregation of proteins, impaired protein degradation, and in turn reduces de novo synthesis of survival-mediating proteins. "

    Full-text · Article · Dec 2015 · Neural Regeneration Research
  • Source
    • "However, excessive and prolonged ER stress reduces the protein synthesis and folding capacity of the ER, and causes accumulation and aggregation of unfolded proteins and subsequent cell death (Schonthal 2012). Therefore, ER stress is thought as a target for therapy in hypoxia-induced neuronal death (Roussel et al. 2013). There is accumulating literature on neuroprotective effects of lithium (Li et al. 2002). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hypoxia is an important cause of brain injury in ischemic stroke. It is known that endoplasmic reticulum (ER) stress is an important determinant of cell survival or death during hypoxia. However, the signaling pathways and molecular mechanisms involved remain to be studied in more detail. To investigate whether inhibition of ER stress promotes neuroprotection pathways, we applied an in vitro oxygen-glucose deprivation (OGD) followed by reoxygenation model of human SK-N-MC neuronal cell cultures in this study. Our results showed that neuronal cell death was induced in this model during the OGD reoxygenation by the sustained ER stress, but not during OGD phase. However, treatment of the cultures with lithium with the OGD reoxygenation insult did not result in neuroprotection, whereas concomitant treatment of chemical chaperon 4-phenylbutyric acid (4-PBA) provides protective effects in ER stress-exposed cells. Moreover, 4-PBA rescued ER stress-suppressed Akt protein biosynthesis, which works cooperatively with lithium in the activation of Akt downstream signaling by inhibition of autophagy-induced cell death. Taken together, our finding provides a possible mechanism by which 4-PBA and lithium contribute to mediate neuroprotection cooperatively. This result may potentially be a useful therapeutic strategy for ischemic stroke.
    Full-text · Article · Mar 2015 · Cellular and Molecular Neurobiology
  • Source
    • "In the CNS, ER stress has been associated with neuronal death in neurodegenerative diseases (Stefani et al., 2012; Roussel et al., 2013), and there is now increasing evidence that ER stress plays a crucial role in hypoxia/ischaemiainduced cell death in vitro (Chen et al., 2008; Roussel et al., 2013) and in vivo (Galehdar et al., 2010; Stefani et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background and purpose: Hypoxia inducible factor-1 (HIF-1) promotes transitory neuronal survival suggesting that additional mechanisms such as the endoplasmic reticulum (ER) stress might be involved in determining neuronal survival or death. Here, we examined the involvement of ER stress in hypoxia-induced neuronal death and analysed the relationship between ER stress and the HIF-1 pathways. Experimental approach: Cultures of rat cortical neurons were exposed to chemical hypoxia induced by 200 μM CoCl2 , and its effect on neuronal viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and counting apoptotic nuclei. Protein levels were determined by Western blot analysis. RT-PCR was performed to analyse the content and the t1/2 of HIF-1α mRNA. Key results: Chemical hypoxia induced neuronal apoptosis in a time-dependent manner and activated the ER stress PRK-like endoplasmic reticulum kinase (PERK)-dependent pathway. At later stages, chemical hypoxia increased the expression of the C/EBP homologous protein (CHOP) and caspase 12 activity. CoCl2 reduced HIF-1α mRNA t1/2 leading to a decrease in HIF-1α mRNA and protein content, simultaneously activating the ER stress PERK-dependent pathway. Salubrinal, a selective inhibitor of phospho-eIF2α phosphatase, protected neurons from chemical hypoxia by reducing CHOP levels and caspase 12 activity, and increasing the t1/2 of HIF-1α mRNA and the levels of HIF-1α protein. Knocking down HIF-1α blocked the neuroprotective effects of salubrinal. Conclusions and implications: Neuronal apoptosis induced by chemical hypoxia is a process regulated by HIF-1α stabilization early on and by ER stress activation at later stages. Our data also suggested that HIF-1α levels were regulated by ER stress.
    Preview · Article · Jan 2015 · British Journal of Pharmacology
Show more