Age-related dysfunctions of the autophagy lysosomal pathway in hippocampal pyramidal neurons under proteasome stress

Gavilán, Elena; Pintado, Cristina; Gavilán, María P.; Daza, Paula; Sánchez‐Aguayo, Inmaculada; Castaño, Angélica; Ruano, Diego

doi:10.1016/j.neurobiolaging.2015.02.025

Cited by 27 publications

(35 citation statements)

References 37 publications

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“…Hence, it is not surprising that recent research has brought the role of UPR in neuroinflammation into focus as a converging pathological pathway. Indeed, recent work has highlighted the existence of a one-directional cause-and-effect relationship between activation of the UPR due to proteasome dysfunction and neurodegeneration (83)(84)(85). Here, our results support a role for the UPR in triggering neuroinflammation, which is a key component of neurodegenerative diseases.…”

Section: Discussionsupporting

confidence: 84%

Molecular Insight Into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain

et al. 2019

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Proteostasis is critical for cells to maintain the balance between protein synthesis, quality control, and degradation. This is particularly important for myeloid cells of the central nervous system as their immunological function relies on proper intracellular protein turnover by the ubiquitin-proteasome system. Accordingly, disruption of proteasome activity due to, e.g., loss-of-function mutations within genes encoding proteasome subunits, results in systemic autoinflammation. On the molecular level, pharmacological inhibition of proteasome results in endoplasmic reticulum (ER) stress-activated unfolded protein response (UPR) as well as an induction of type I interferons (IFN). Nevertheless, our understanding as to whether and to which extent UPR signaling regulates type I IFN response is limited. To address this issue, we have tested the effects of proteasome dysfunction upon treatment with proteasome inhibitors in primary murine microglia and microglia-like cell line BV-2. Our data show that proteasome impairment by bortezomib is a stimulus that activates all three intracellular ER-stress transducers activation transcription factor 6, protein kinase R-like endoplasmic reticulum kinase and inositol-requiring protein 1 alpha (IRE1α), causing a full activation of the UPR. We further demonstrate that impaired proteasome activity in microglia cells triggers an induction of IFNβ1 in an IRE1-dependent manner. An inhibition of the IRE1 endoribonuclease activity significantly attenuates TANK-binding kinase 1-mediated activation of type I IFN. Moreover, interfering with TANK-binding kinase 1 activity also compromised the expression of C/EBP homologous protein 10, thereby emphasizing a multilayered interplay between UPR and type IFN response pathway. Interestingly, the induced protein kinase R-like endoplasmic reticulum kinase-activation transcription factor 4-C/EBP homologous protein 10 and IRE1-X-box-binding protein 1 axes caused a significant upregulation of proinflammatory cytokine interleukin 6 expression that exacerbates STAT1/STAT3 signaling in cells with dysfunctional proteasomes. Altogether, these findings indicate that proteasome impairment disrupts ER homeostasis and triggers a complex interchange between ER-stress sensors and type I IFN signaling, thus inducing in myeloid cells a state of chronic inflammation.

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Section: Discussionsupporting

confidence: 84%

Molecular Insight Into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain

et al. 2019

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“…Next, we searched for the cellular pathways that might be involved in LPS-induced autophagy activation. Based on previous data we first focused on the Akt/GSK-3β/βcatenin axis 1 , 21 . As shown, LPS injection induced early Akt activation as indicated the higher amount of both phosphoSer473Akt (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Neuroinflammation and proteostasis disruption are characteristics of normal aging and some age-related neurodegenerative diseases. Cellular proteostasis is mainly sustained by the ubiquitin proteasome system and autophagy, which could act coordinately under specific situations 1 . A consequence of proteostasis alteration is ER-stress.…”

Section: Introductionmentioning

confidence: 99%

Neuroinflammation alters cellular proteostasis by producing endoplasmic reticulum stress, autophagy activation and disrupting ERAD activation

Pintado

Macias

Dominguez-Martín

et al. 2017

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Proteostasis alteration and neuroinflammation are typical features of normal aging. We have previously shown that neuroinflammation alters cellular proteostasis through immunoproteasome induction, leading to a transient decrease of proteasome activity. Here, we further investigated the role of acute lipopolysaccharide (LPS)-induced hippocampal neuroinflammation in cellular proteostasis. In particular, we focused on macroautophagy (hereinafter called autophagy) and endoplasmic reticulum-associated protein degradation (ERAD). We demonstrate that LPS injection induced autophagy activation that was dependent, at least in part, on glycogen synthase kinase (GSK)-3β activity but independent of mammalian target of rapamycin (mTOR) inhibition. Neuroinflammation also produced endoplasmic reticulum (ER) stress leading to canonical unfolded protein response (UPR) activation with a rapid activating transcription factor (ATF) 6α attenuation that resulted in a time-dependent down-regulation of ERAD markers. In this regard, the time-dependent accumulation of unspliced X-box binding protein (XBP) 1, likely because of decreased inositol-requiring enzyme (IRE) 1α-mediated splicing activity, might underlie in vivo ATF6α attenuation. Importantly, lactacystin-induced activation of ERAD was abolished in both the acute neuroinflammation model and in aged rats. Therefore, we provide a cellular pathway through which neuroinflammation might sensitize cells to neurodegeneration under stress situations, being relevant in normal aging and other disorders where neuroinflammation is a characteristic feature.

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“…Autophagy is a degradation process that plays a pivotal role in the cellular energy balance and in eliminating misfolded proteins in cells (22). Autophagy is classified as macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) (23, 24).…”

Section: Introductionmentioning

confidence: 99%

Iron Deposition Leads to Neuronal α-Synuclein Pathology by Inducing Autophagy Dysfunction

et al. 2017

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Growing evidence has indicated that iron deposition in the substantia nigra plays an important role in Parkinson’s disease (PD). However, the underlying mechanism is still elusive. Using primary dopaminergic neurons and SH-SY5Y cells cultured in vitro, we observed that iron loading increased α-synuclein and reactive oxygen species (ROS) levels in these cells but did not affect the intracellular α-synuclein mRNA levels. Furthermore, iron loading significantly downregulated Beclin-1 levels and decreased the ratio of microtubule-associated protein 1 light chain 3 isoforms (LC3 II/LC3 I). However, a significant change in the levels of autophagy-related gene 5 (Atg5) was not observed in either neurons or SH-SY5Y cells after iron treatment. After treatment with rapamycin, the iron loading-induced increase in the α-synuclein level was significantly reversed and ROS generation was alleviated in both cultured neurons and SH-SY5Y cells. These results indicate that the inhibition of autophagy is critical for the pathological alterations in α-synuclein induced by iron loading. Moreover, treatment with vitamin E did not affect the increase in the α-synuclein levels but significantly eliminated the iron-induced ROS production. Together, our study shows that autophagy dysfunction contributes to iron-induced α-synuclein pathology.

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Age-related dysfunctions of the autophagy lysosomal pathway in hippocampal pyramidal neurons under proteasome stress

Cited by 27 publications

References 37 publications

Molecular Insight Into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain

Molecular Insight Into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain

Neuroinflammation alters cellular proteostasis by producing endoplasmic reticulum stress, autophagy activation and disrupting ERAD activation

Iron Deposition Leads to Neuronal α-Synuclein Pathology by Inducing Autophagy Dysfunction

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