Artificial enforcement of the unfolded protein response (UPR) reduces disease features in multiple preclinical models of ALS/FTD.

Amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) are part of a spectrum of diseases that share several causative genes, resulting in a combinatory of motor and cognitive symptoms and abnormal protein aggregation. Multiple unbiased studies have revealed that proteostasis impairment at the level of the endoplasmic reticulum (ER) is a transversal pathogenic feature of ALS/FTD. The transcription factor XBP1s is a master regulator of the unfolded protein response (UPR), the main adaptive pathway to cope with ER stress.

Central role of the ER proteostasis network in healthy aging.

Aging trajectories vary among individuals, characterized by progressive functional decline, often leading to disease states. One of the central hallmarks of aging is the deterioration of proteostasis, where the function of the endoplasmic reticulum (ER) is dramatically affected. ER stress is monitored and adjusted by the unfolded protein response (UPR); a signaling pathway that mediates adaptive processes to restore proteostasis.

The UPRising connection between endoplasmic reticulum stress and the tumor microenvironment.

The tumor microenvironment (TME) represents a dynamic network of cancer cells, stromal cells, immune mediators, and extracellular matrix components, crucial for cancer progression. Stress conditions such as oncogene activation, nutrient deprivation, and hypoxia disrupt the endoplasmic reticulum (ER), activating the unfolded protein response (UPR), the main adaptive mechanism to restore ER function. The UPR regulates cancer progression by engaging cell-autonomous and cell-non-autonomous mechanisms, reprogramming the stroma and promoting immune evasion, angiogenesis, and invasion.

IRE1α Mediates the Hypertrophic Growth of Cardiomyocytes Through Facilitating the Formation of Initiation Complex to Promote the Translation of TOP-Motif Transcripts.

Background: Cardiomyocyte growth is coupled with active protein synthesis, which is one of the basic biological processes in living cells. However, it is unclear whether the unfolded protein response transducers and effectors directly take part in the control of protein synthesis. The connection between critical functions of the unfolded protein response in cellular physiology and requirements of multiple processes for cell growth prompted us to investigate the role of the unfolded protein response in cell growth and underlying molecular mechanisms.

ER stress signaling at the interphase between MASH and HCC.

HCC is the most frequent primary liver cancer with an extremely poor prognosis and often develops on preset of chronic liver diseases. Major risk factors for HCC include metabolic dysfunction-associated steatohepatitis, a complex multifactorial condition associated with abnormal endoplasmic reticulum (ER) proteostasis. To cope with ER stress, the unfolded protein response engages adaptive reactions to restore the secretory capacity of the cell.

The ER stress sensor IRE1 interacts with STIM1 to promote store-operated calcium entry, T cell activation, and muscular differentiation.

Store-operated Ca entry (SOCE) mediated by stromal interacting molecule (STIM)-gated ORAI channels at endoplasmic reticulum (ER) and plasma membrane (PM) contact sites maintains adequate levels of Ca within the ER lumen during Ca signaling. Disruption of ER Ca homeostasis activates the unfolded protein response (UPR) to restore proteostasis. Here, we report that the UPR transducer inositol-requiring enzyme 1 (IRE1) interacts with STIM1, promotes ER-PM contact sites, and enhances SOCE.

IGF2 prevents dopaminergic neuronal loss and decreases intracellular alpha-synuclein accumulation in Parkinson's disease models.

Parkinson's disease (PD) is the second most common late-onset neurodegenerative disease and the predominant cause of movement problems. PD is characterized by motor control impairment by extensive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). This selective dopaminergic neuronal loss is in part triggered by intracellular protein inclusions called Lewy bodies, which are composed mainly of misfolded alpha-synuclein (α-syn) protein.

Immunohistochemical characterisation of the adult Nothobranchius furzeri intestine.

Nothobranchius furzeri is emerging as an exciting vertebrate organism in the field of biomedicine, developmental biology and ecotoxicology research. Its short generation time, compressed lifespan and accelerated ageing make it a versatile model for longitudinal studies with high traceability. Although in recent years the use of this model has increased enormously, there is still little information on the anatomy, morphology and histology of its main organs.

c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration.

The endoplasmic reticulum is a subcellular organelle key in the control of synthesis, folding, and sorting of proteins. Under endoplasmic reticulum stress, an adaptative unfolded protein response is activated; however, if this activation is prolonged, cells can undergo cell death, in part due to oxidative stress and mitochondrial fragmentation. Here, we report that endoplasmic reticulum stress activates c-Abl tyrosine kinase, inducing its translocation to mitochondria.

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 (CCl ) administration or by high fat diet.

Calcium signaling in lysosome-dependent cell death.

Calcium is a crucial messenger of intracellular and extracellular signals, regulating a great variety of cellular processes such as cell death, proliferation, and metabolism. Inside the cell, calcium signaling is one of the main interorganelle communication mediators, with central functional roles at the endoplasmic reticulum (ER), mitochondria, Golgi complex, and lysosomes. Lysosomal function is highly dependent on lumenal calcium and most of the lysosomal membrane-localised ion channels regulate several lysosomal functions and properties such as lumenal pH.

Apoptotic cell death in disease-Current understanding of the NCCD 2023.

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions.

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 Alzheimer's 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) 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).

Proteomic Analysis of Huntington's Disease Medium Spiny Neurons Identifies Alterations in Lipid Droplets.

Huntington's disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion in the Huntingtin (HTT) gene. The resulting polyglutamine (polyQ) tract alters the function of the HTT protein. Although HTT is expressed in different tissues, the medium-spiny projection neurons (MSNs) in the striatum are particularly vulnerable in HD.

Mitochondria-associated niches in health and disease.

The appreciation of the importance of interorganelle contacts has steadily increased over the past decades. Advances in imaging, molecular biology and bioinformatic techniques allowed the discovery of new mechanisms involved in the interaction and communication between organelles, providing novel insights into the inner works of a cell. In this Review, with the mitochondria under the spotlight, we discuss the most recent findings on the mechanisms mediating the communication between organelles, focusing on Ca2+ signaling, lipid exchange, cell death and stress responses.

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

Aging is a major risk factor to develop 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.

Balancing energy and protein homeostasis at ER-mitochondria contact sites.

The endoplasmic reticulum (ER) is the largest organelle of the cell and participates in multiple essential functions, including the production of secretory proteins, lipid synthesis, and calcium storage. Sustaining proteostasis requires an intimate coupling with energy production. Mitochondrial respiration evolved to be functionally connected to ER physiology through a physical interface between both organelles known as mitochondria-associated membranes.

Neuronal Rubicon Represses Extracellular APP/Amyloid β Deposition in Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent age-associated neurodegenerative disease. A decrease in autophagy during aging contributes to brain disorders by accumulating potentially toxic substrates in neurons. Rubicon is a well-established inhibitor of autophagy in all cells.

Critical roles of protein disulfide isomerases in balancing proteostasis in the nervous system.

Protein disulfide isomerases (PDIs) constitute a family of oxidoreductases promoting redox protein folding and quality control in the endoplasmic reticulum. PDIs catalyze disulfide bond formation, isomerization, and reduction, operating in concert with molecular chaperones to fold secretory cargoes in addition to directing misfolded proteins to be refolded or degraded. Importantly, PDIs are emerging as key components of the proteostasis network, integrating protein folding status with central surveillance mechanisms to balance proteome stability according to cellular needs.