Biology subjects

Tamburini, G.

Publications and source records attributed to Tamburini, G..

5 recordsLinked to original sources

bioRxiv2026

Optimized AAV to express the unfolded protein response transcription factor XBP1s ameliorates Alzheimer's disease features in mouse models

Proteostasis impairment at the level of the endoplasmic reticulum (ER) is a salient feature of Alzheimers disease (AD). The unfolded protein response (UPR) is the main pathway to cope with ER stress, where the expression of the transcription factor X-Box binding protein 1 (XBP1) is central to establish repair programs. To artificially enforce the adaptive capacity of the UPR in the AD brain, we recently reported the protective effects of overexpressing active XBP1 in the brain using adeno-associated vectors (AAVs) of AD mice, in addition to aged animals. Here we have generated a next generation vector suitable for clinical testing by (i) expressing codon-optimized human XBP1s without artificial tags, (ii) the use of the synapsin promoter to restrict expression to neurons, and (iii) incorporating a novel variant of AAV2 (AAV-TT) with greater biodistribution (here termed Proteostaser-1). Treatment of 5xFAD mice with Proteostaser-1 improved spatial learning and synaptic plasticity, and reduced the deposition of amyloid plaques in the brain. Proteostaser-1 administration also improved cognition in a model of sporadic AD based on the intracerebral injection of amyloid {beta} oligomers. Our results further support the therapeutic potential of the UPR as a strategy to ameliorate AD features and sustain synaptic function.

cell biology↗

bioRxiv2024

BAX and BAK expression triggers multiple IRE1 signaling outputs under ER stress

Adaptation to endoplasmic reticulum (ER) stress depends on the activation of the unfolded protein response (UPR) stress sensor inositol-requiring enzyme 1 alpha (IRE1). IRE1 is a central ER stress sensors, that signals through the activation of its RNase domain to catalyze the splicing the mRNA encoding the transcription factor X-box binding protein 1 (XBP1), resulting on the expression of a stable and active transcription factor termed XBP1s. The kinetics and amplitude of IRE1 signaling are regulated by different posttranslational modifications and the physical interaction of different factors. Early studies demonstrated that the expression of the proapoptotic proteins BAX and BAX enhance UPR signaling. However, the possible effects on the RNase activity were not defined. Here we provide preliminary evidence indicating that BAX and BAK deficiency increases the in 10 folds the threshold of ER stress to induce XBP1 mRNA splicing, and the upregulation of its target genes. In addition, the degradation of RIDD substrates was strongly reduced in BAX and BAK null cells. BAX and BAK double deficiency also attenuated the levels of IRE1 phosphorylation under mild ER stress. These results reinforce previous findings indicating that proapoptotic BAX and BAK have alternative functions at the ER regulating the UPR.

cell biology↗

bioRxiv2023

The endoplasmic reticulum stress sensor IRE1 regulates collagen secretion through the enforcement of the proteostasis factor P4HB/PDIA1 contributing to liver damage and fibrosis

Collagen is one the most abundant proteins and the main cargo of the secretory pathway, contributing to hepatic fibrosis and cirrhosis due to excessive deposition of extracellular matrix. Here we investigated the possible contribution of the unfolded protein response, the main adaptive pathway that monitors and adjusts the protein production capacity at the endoplasmic reticulum, to collagen biogenesis and liver disease. Genetic ablation of the ER stress sensor IRE1 reduced liver damage and diminished collagen deposition in models of liver fibrosis triggered by carbon tetrachloride (CCl4) administration or by high fat diet. Proteomic and transcriptomic profiling identified the prolyl 4-hydroxylase (P4HB, also known as PDIA1), which is known to be critical for collagen maturation, as a major IRE1-induced gene. Cell culture studies demonstrated that IRE1 deficiency results in collagen retention at the ER and altered secretion, a phenotype rescued by P4HB overexpression. Taken together, our results collectively establish a role of the IRE1/P4HB axis in the regulation of collagen production and its significance in the pathogenesis of various disease states.

cell biology↗

bioRxiv2022

The unfolded protein response transcription factor XBP1s ameliorates Alzheimer`s disease by improving synaptic function and proteostasis

Alteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimers disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER. Inositol requiring enzyme-1 (IRE1) is an ER-located kinase and endoribonuclease that operates as a central ER stress sensor, enabling the establishment of adaptive and repair programs through the control of the expression of the transcription factor X-Box binding protein 1 (XBP1). A polymorphism in the XBP1 promoter has been suggested as a risk factor for AD. To artificially enforce the adaptive capacity of the UPR in the AD brain, we developed strategies to express the active form of XBP1 in neurons using preclinical models. Overexpression of an active form of XBP1 in the nervous system using transgenic mice significantly reduced the load of amyloid deposits in the cerebral cortex and hippocampus and preserved synaptic and cognitive function. Moreover, local delivery of XBP1 into the hippocampus of an AD mice using adeno-associated vectors improved long-term potentiation, memory performance, and dendritic spine density. Quantitative proteomics of the hippocampus revealed that XBP1 expression corrects a large proportion of the alterations observed in the 5xFAD model, restoring the levels of several synaptic proteins and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of targeting UPR-dependent gene expression programs as a strategy to ameliorate AD features and sustain synaptic function.

animal behavior and cognition↗

bioRxiv2020

Control of mammalian brain aging by the unfolded protein response (UPR)

Aging is the major risk factor for the development of dementia and neurodegenerative disorders, and the aging brain manifests severe deficits in buffering capacity by the proteostasis network. Accordingly, we investigated the significance of the unfolded protein response (UPR), a major signaling pathway that copes with endoplasmic reticulum (ER) stress, to normal mammalian brain aging. Genetic disruption of ER stress sensor IRE1 accelerated cognitive and motor dysfunction during aging. Exogenous bolstering of the UPR by overexpressing an active form of the transcription factor XBP1 restored synaptic and cognitive function in addition to reducing cell senescence. Remarkably, proteomic profiling of hippocampal tissue indicated that XBP1s expression corrected age-related alterations in synaptic function. Collectively, our data demonstrate that strategies to manipulate the UPR sustain healthy brain aging. One Sentence SummaryThe IRE1/XBP1 pathway dictates when and how brain function declines during aging.

neuroscience↗