Soledad Matus

Lysophosphatidic acid (LPA) is a bioactive lipid that signals through G protein–coupled receptors (LPA _1–6 ) and regulates multiple cellular processes, including fibrosis. Although LPA signaling has been implicated in fibrotic diseases in several organs, its role in skeletal muscle remains unclear. Here, we show that LPA/LPA ₁ signaling promotes fibrogenesis after sciatic nerve transection. Denervation induces differential expression of LPA signaling axis components and a transient early increase in intramuscular LPA levels. Pharmacological inhibition of LPA _1/3 with Ki16425, or genetic deletion of LPA ₁ , reduces extracellular matrix accumulation and expansion of fibro/adipogenic progenitors (FAPs) in denervated muscle. Although LPA blockade suppresses atrophy-related gene expression, it does not fully preserve myofiber size. Mechanistically, denervation increases YAP/TAZ expression, nuclear localization in FAPs, and transcriptional activity, effects that are attenuated by LPA axis inhibition. Furthermore, pharmacological inhibition of YAP/TAZ with verteporfin reduces fibrosis after denervation, supporting their role as critical downstream mediators. Finally, transient denervation activates the LPA axis, promotes muscle fibrosis, reduces axonal density in the sciatic nerve, and increases neuromuscular junction instability, effects reversed by Ki16425. Together, these findings identify the LPA/LPA ₁ /YAP/TAZ pathway as a key driver of denervation-induced muscle fibrosis and a potential therapeutic target in neuromuscular disorders.

Under conditions of amino acid deficiency, mammalian cells activate a nutrient-sensing kinase known as general control nonderepressible 2 (GCN2). The activation of GCN2 results in the phosphorylation of the alpha subunit of the eukaryotic initiation factor 2 (eIF2α), which can be phosphorylated by three other three integrated stress response (ISR) kinases, reducing overall protein synthesis. GCN2 activation also promotes the translation of specific mRNAs, some of which encode transcription factors that enhance the transcription of genes involved in the synthesis, transport, and metabolism of amino acids to restore cellular homeostasis. The phosphorylation of eIF2α has been shown to protect oligodendrocytes, the cells responsible for producing myelin in the central nervous system during remyelination. Here, we explore the potential role of the kinase GCN2 in the myelination process. We challenged mice deficient in the GCN2-encoding gene with a pharmacological demyelinating stimulus (cuprizone) and evaluated the recovery of myelin as well as ISR activation through the levels of eIF2α phosphorylation. Our findings indicate that GCN2 controls the establishment of myelin by fine-tuning its abundance and morphology in the central nervous system. We also found that GCN2 is essential for remyelination. Surprisingly, we discovered that GCN2 is necessary to maintain eIF2α levels during remyelination.

Sjögren’s disease is a chronic autoimmune disease characterized by symptoms of oral and ocular dryness and extraglandular manifestations. Mouth dryness is not only due to reduced saliva volume, but also to alterations in the quality of salivary mucins in patients with Sjögren’s disease. Mucins play a leading role in mucosa hydration and protection, where sulfated and sialylated oligosaccharides retain water molecules at the epithelial surface. The correct localization of glycosyltransferases and sulfotransferases within the Golgi apparatus determines adequate O-glycosylation and sulfation of mucins, which depends on specific golgins that tether enzyme-bearing vesicles. Here, we show that a golgin called Giantin was mislocalized in salivary glands from patients with Sjögren’s disease and formed protein complexes with Gal3-O-sulfotransferases (Gal3STs), which changed their localization in Giantin-knockout and -knockdown cells. Our results suggest that Giantin could tether Gal3ST-bearing vesicles and that its altered localization could affect Gal3ST activity, explaining the decreased sulfation of MUC5B observed in salivary glands from patients with Sjögren’s disease.

There is a growing evidence describing a decline in adaptive homeostasis in aging-related diseases affecting the central nervous system (CNS), many of which are characterized by the appearance of non-native protein aggregates. One signaling pathway that allows cell adaptation is the integrated stress response (ISR), which senses stress stimuli through four kinases. ISR activation promotes translational arrest through the phosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2α) and the induction of a gene expression program to restore cellular homeostasis. However, depending on the stimulus, ISR can also induce cell death. One of the ISR sensors is the double-stranded RNA-dependent protein kinase [protein kinase R (PKR)], initially described as a viral infection sensor, and now a growing evidence supports a role for PKR on CNS physiology. PKR has been largely involved in the Alzheimer’s disease (AD) pathological process. Here, we reviewed the antecedents supporting the role of PKR on the efficiency of synaptic transmission and cognition. Then, we review PKR’s contribution to AD and discuss the possible participation of PKR as a player in the neurodegenerative process involved in aging-related pathologies affecting the CNS.

Aging is a complex process in which the accumulation of molecular, cellular, and organism dysfunction increases the probability of death. Several pieces of evidence have revealed a contribution of stress responses in aging and in aging-related diseases, in particular, the key role of signaling pathways associated to nutritional stress. Here, we review the possible interplay between amino acid sensing and redox balance maintenance mediated by the nutritional sensor general control nonderepressive 2 (GCN2). We discuss this new dimension of nutritional stress sensing consequences, standing out GCN2 as a central coordinator of key cellular processes that assure healthy homeostasis in the cell, raising GCN2 as a novel interesting target, that when activated, could imply pleiotropic benefits, particularly GCN2 intervention and its new unexplored therapeutic role as a player in the aging process.

Amyotrophic lateral sclerosis (ALS) is a multifactorial fatal motoneuron disease without a cure. Ten percent of ALS cases can be pointed to a clear genetic cause, while the remaining 90% is classified as sporadic. Our study was aimed to uncover new connections within the ALS network through a bioinformatic approach, by which we identified C13orf18, recently named Pacer, as a new component of the autophagic machinery and potentially involved in ALS pathogenesis. Initially, we identified Pacer using a network-based bioinformatic analysis. Expression of Pacer was then investigated in vivo using spinal cord tissue from two ALS mouse models (SOD1G93A and TDP43A315T) and sporadic ALS patients. Mechanistic studies were performed in cell culture using the mouse motoneuron cell line NSC34. Loss of function of Pacer was achieved by knockdown using short-hairpin constructs. The effect of Pacer repression was investigated in the context of autophagy, SOD1 aggregation, and neuronal death. Using an unbiased network-based approach, we integrated all available ALS data to identify new functional interactions involved in ALS pathogenesis. We found that Pacer associates to an ALS-specific subnetwork composed of components of the autophagy pathway, one of the main cellular processes affected in the disease. Interestingly, we found that Pacer levels are significantly reduced in spinal cord tissue from sporadic ALS patients and in tissues from two ALS mouse models. In vitro, Pacer deficiency lead to impaired autophagy and accumulation of ALS-associated protein aggregates, which correlated with the induction of cell death. This study, therefore, identifies Pacer as a new regulator of proteostasis associated with ALS pathology.

Tar DNA binding protein 43 (TDP-43) is the principal component of ubiquitinated protein inclusions present in nervous tissue of most cases of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previous studies described a TDP-43^A315T transgenic mouse model that develops progressive motor dysfunction in the absence of protein aggregation or significant motoneuron loss, questioning its validity to study ALS. Here we have further characterized the course of the disease in TDP-43^A315T mice using a battery of tests and biochemical approaches. We confirmed that TDP-43 mutant mice develop impaired motor performance, accompanied by progressive body weight loss. Significant differences were observed in life span between genders, where females survived longer than males. Histopathological analysis of the spinal cord demonstrated a significant motoneurons loss, accompanied by axonal degeneration, astrogliosis and microglial activation. Importantly, histopathological alterations observed in TDP-43 mutant mice were similar to some characteristic changes observed in mutant SOD1 mice. Unexpectedly, we identified the presence of different species of disulfide-dependent TDP-43 aggregates in cortex and spinal cord tissue. Overall, this study indicates that TDP-43^A315T transgenic mice develop key features resembling key aspects of ALS, highlighting its relevance to study disease pathogenesis.