Loss of XBP1 accelerates age-related decline in retinal function and neurodegeneration

McLaughlin, Todd; Falkowski, Marek; Park, Jae Whan; Keegan, S.; Elliott, Michael H.; Wang, Joshua J.; Zhang, Sarah X.

doi:10.1186/s13024-018-0250-z

Cited by 35 publications

(49 citation statements)

References 28 publications

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“…Mouse eye cryosections were prepared for immunohistochemistry as described previously (McLaughlin et al, 2018 ). The primary antibodies used were: Ribeye (Synaptic Systems 192003, 1:800); PKCα (Santa Cruz sc-8393, 1:400); Pax6 (DSHB Pax6-s, 1:25); and calretinin (Millipore Mab1658, 1:800).…”

Section: Methodsmentioning

confidence: 99%

p58IPK Is an Endogenous Neuroprotectant for Retinal Ganglion Cells

McLaughlin

Dhimal

et al. 2018

Front. Aging Neurosci.

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p58IPK is an endoplasmic reticulum (ER)-resident chaperone playing a critical role in facilitating protein folding and protein homeostasis. Previously, we have demonstrated that p58IPK is expressed broadly in retinal neurons including retinal ganglion cells (RGCs) and loss of p58IPK results in age-related RGC degeneration. In the present study, we investigate the role of p58IPK in neuroprotection by in vitro and in vivo studies using primary RGC culture and two well-established disease-relevant RGC injury models: retinal ischemia/reperfusion (I/R) and microbead-induced ocular hypertension. Our results demonstrate that in both in vivo models, p58IPK −/− mice exhibit significantly increased RGC loss compared to wild type (WT) mice. In vitro, p58IPK-deficient RGCs show reduced viability and are more susceptible to cell death induced by the ER stress inducer tunicamycin (TM). Overexpression of p58IPK by adeno-associated virus (AAV) significantly diminishes TM-induced cell death in both WT and p58IPK −/− RGCs. Interestingly, we find that loss of p58IPK leads to reduced mRNA expression, but not the protein level, of mesencephalic astrocyte-derived neurotrophic factor (MANF), a neurotrophic factor that resides in the ER. Treatment with recombinant MANF protein protects R28 retinal neural cells and mouse retinal explants from TM-induced cell death. Taken together, our study suggests that p58IPK functions as an endogenous neuroprotectant for RGCs. The mechanisms underlying p58IPK’s neuroprotective action and the potential interactions between p58IPK and MANF warrant future investigation.

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Section: Methodsmentioning

confidence: 99%

p58IPK Is an Endogenous Neuroprotectant for Retinal Ganglion Cells

McLaughlin

Dhimal

et al. 2018

Front. Aging Neurosci.

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“…XBP1s is an important gene that turns on transcription of a subset of ER chaperones genes in response to stress. Previous studies have reported a pivotal role of XBP1 in the development of several diseases such as Alzheimer's Disease [43], diabetic retinopathy [44], neurodegeneration [45], insulin resistance [46], and obesity [47]. Sha et al [48] demonstrated that XBP1s improves glucose tolerance and insulin sensitivity in both lean and obese (ob/ob) mice by promoting adiponectin multimerization.…”

Section: Discussionmentioning

confidence: 99%

Beneficial effect of ER stress preconditioning in protection against FFA-induced adipocyte inflammation via XBP1 in 3T3-L1 adipocytes

et al. 2019

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Adipose tissue inflammation is closely associated with the development of obesity and insulin resistance. Free fatty acids (FFAs) are a major inducer of obesity-related insulin resistance. Previously, we reported that endoplasmic reticulum (ER) stress potentially mediated retinal inflammation in diabetic retinopathy. The unfolded protein response (UPR) protects cells against damage induced by oxidative stress. X-box binding protein 1 (XBP1) plays a major role in protecting cells by modulating the UPR. However, the link between ER stress and adipocyte inflammation has been poorly investigated. In the present study, we found that pretreatment of 3T3-L1 adipocytes with a low dose of ER stress inducer tunicamycin inhibited FFAinduced upregulated expression of inflammatory cytokines. In addition, FFAs induced phosphorylation of the p65 subunit of NF-κB was largely inhibited by pretreatment with tunicamycin in 3T3-L1 adipocytes. Knockdown of XBP1 by siRNA markedly mitigated the protective effects of preconditioning against inflammation. Conversely, overexpression of XBP1 alleviated FFA-induced phosphorylation of IκB-α, IKKα/β, and NF-κB, which was accompanied by decreased inflammatory cytokine expression. Collectively, these results imply a beneficial role of ER stress preconditioning in protecting against FFAinduced 3T3-L1 adipocyte inflammation, which is likely mediated through inhibition of the IKK/NF-κB pathway via XBP1.

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“…The ER does not need to be physically malformed to contribute to neurological disease, as ER stress has been linked to several neurodegenerative conditions (Hetz and Mollereau, 2014;Plate and Wiseman, 2017;Martínez et al, 2018;McLaughlin et al, 2018;Morris et al, 2018). ER stress occurs when the amount of unfolded proteins in the ER reaches an unmanageable level, triggering the unfolded protein response (UPR) (Martínez et al, 2018).…”

Section: Protein Synthesis Linked To Neurological Diseasementioning

confidence: 99%

Homeostatic Roles of the Proteostasis Network in Dendrites

Lottes

Cox

2020

Front. Cell. Neurosci.

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Cellular protein homeostasis, or proteostasis, is indispensable to the survival and function of all cells. Distinct from other cell types, neurons are long-lived, exhibiting architecturally complex and diverse multipolar projection morphologies that can span great distances. These properties present unique demands on proteostatic machinery to dynamically regulate the neuronal proteome in both space and time. Proteostasis is regulated by a distributed network of cellular processes, the proteostasis network (PN), which ensures precise control of protein synthesis, native conformational folding and maintenance, and protein turnover and degradation, collectively safeguarding proteome integrity both under homeostatic conditions and in the contexts of cellular stress, aging, and disease. Dendrites are equipped with distributed cellular machinery for protein synthesis and turnover, including dendritically trafficked ribosomes, chaperones, and autophagosomes. The PN can be subdivided into an adaptive network of three major functional pathways that synergistically govern protein quality control through the action of (1) protein synthesis machinery; (2) maintenance mechanisms including molecular chaperones involved in protein folding; and (3) degradative pathways (e.g., Ubiquitin-Proteasome System (UPS), endolysosomal pathway, and autophagy. Perturbations in any of the three arms of proteostasis can have dramatic effects on neurons, especially on their dendrites, which require tightly controlled homeostasis for proper development and maintenance. Moreover, the critical importance of the PN as a cell surveillance system against protein dyshomeostasis has been highlighted by extensive work demonstrating that the aggregation and/or failure to clear aggregated proteins figures centrally in many neurological disorders. While these studies demonstrate the relevance of derangements in proteostasis to human neurological disease, here we mainly review recent literature on homeostatic developmental roles the PN machinery plays in the establishment, maintenance, and plasticity of stable and dynamic dendritic arbors. Beyond basic housekeeping functions, we consider roles of PN machinery in protein quality control mechanisms linked to dendritic plasticity (e.g., dendritic spine remodeling during LTP); cell-type specificity; dendritic morphogenesis; and dendritic pruning.

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Loss of XBP1 accelerates age-related decline in retinal function and neurodegeneration

Cited by 35 publications

References 28 publications

p58IPK Is an Endogenous Neuroprotectant for Retinal Ganglion Cells

p58IPK Is an Endogenous Neuroprotectant for Retinal Ganglion Cells

Beneficial effect of ER stress preconditioning in protection against FFA-induced adipocyte inflammation via XBP1 in 3T3-L1 adipocytes

Homeostatic Roles of the Proteostasis Network in Dendrites

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