bims-ershed 2022-11-06 papers

Ageing Res Rev. 2022 Nov 01. pii: S1568-1637(22)00216-1. [Epub ahead of print] 101774

The functions of IRE1α in neurodegenerative diseases: Beyond ER stress.

Ling Chen, Mingxia Bi, Zhen Zhang, Xixun Du, Xi Chen, Qian Jiao, Hong Jiang.

Inositol-requiring enzyme 1 α (IRE1α) is a type I transmembrane protein that resides in the endoplasmic reticulum (ER). IRE1α, which is the primary sensor of ER stress, has been proven to maintain intracellular protein homeostasis by activating X-box binding protein 1 (XBP1). Further studies have revealed novel physiological functions of the IRE1α, such as its roles in mRNA and protein degradation, inflammation, immunity, cell proliferation and cell death. Therefore, the function of IRE1α is not limited to its role in ER stress; IRE1α is also important for regulating other processes related to cellular physiology. Furthermore, IRE1α is a significant factor in the regulation of neurodegenerative diseases that are caused by the phosphorylation of Tau protein, the accumulation of α-synuclein (α-syn) and the toxic effects of mutant Htt (mHtt). Therefore, targeting IRE1α is a valuable approach for treating neurodegenerative diseases and regulating cell function. This review discusses the role of IRE1α in different cellular processes, and emphasizes the importance of IRE1α in neurodegenerative diseases.

Keywords: ER stress; IRE1α; XBP1; neurodegenerative diseases

DOI: https://doi.org/10.1016/j.arr.2022.101774

EMBO J. 2022 Oct 31. e111952

Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging.

Aging is a major risk factor for neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors associated with synaptic function and pathways linked to neurodegenerative diseases. Similar changes were observed in human brain aging. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

Keywords: ER stress; UPR; XBP1s; aging brain; proteostasis

DOI: https://doi.org/10.15252/embj.2022111952

Front Cell Neurosci. 2022 ;16 1016391

Beneficial effects of neuronal ATF6 activation in permanent ischemic stroke.

Xuan Li, Ran Li, Liping Lu, Ashis Dhar, Huaxin Sheng, Wei Yang.

Objective: Brain ischemia leads to the accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) lumen and consequently, ER stress. To help cells restore ER function, a series of adaptive stress response pathways, collectively termed the unfolded protein response (UPR), are activated. We have previously demonstrated that the UPR pathway initiated by ATF6 is pro-survival in transient ischemic stroke. However, the effect of ATF6 activation on the outcome after permanent ischemic stroke remains unknown. Here, we addressed this knowledge gap. Method: sATF6-KI mice with functional short-form ATF6 (sATF6) predominantly expressed in forebrain neurons were subjected to two ischemic stroke models: photothrombotic stroke and permanent middle cerebral artery occlusion (pMCAO). Both short-term and long-term functional outcomes were evaluated. Changes in neuroinflammation and cerebrovascular density after pMCAO were also assessed. Results: Compared to littermate controls, sATF6-KI mice performed significantly better in open field, cylinder, and foot fault tests on day 1 or 3 after photothrombotic stroke. However, on days 7 and 14 after stroke, the performance of these functional tests was not significantly different between groups, which is likely related to mild brain damage associated with this stroke model. Thus, to evaluate the long-term effects of ATF6 activation in permanent stroke, we turned to our pMCAO model. We first found that on day 4 after pMCAO, functional outcome was better, and infarct volumes were smaller in sATF6-KI mice vs controls. Next, the 15-day stroke outcome study indicated that compared to control mice, sATF6-KI mice consistently exhibited improved performance in neurologic scoring, tight rope test, and tape removal test, after pMCAO. Moreover, sATF6-KI mice showed higher vascular density and lower activation of both astrocytes and microglia around stroke regions on day 16 after pMCAO. Conclusions: Here, we presented the first evidence that activation of the ATF6 UPR branch is protective in permanent ischemic stroke, which further supports the therapeutic potential of targeting the ATF6 pathway in stroke.

Keywords: ER stress; MCAO; UPR; long-term; photothrombotic stroke; proteostasis; transgenic mice

DOI: https://doi.org/10.3389/fncel.2022.1016391