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Altered proteostasis is a salient feature of Alzheimer’s disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress and abnormal protein aggregation. ER stress triggers the activation of the unfolded protein response (UPR), a signaling pathway that enforces adaptive programs to sustain proteostasis or eliminate terminally damaged cells. IRE1 is an ER-located kinase and endoribonuclease that operates as a major stress transducer, mediating both adaptive and proapoptotic programs under ER stress. IRE1 signaling controls the expression of the transcription factor XBP1, in addition to degrade several RNAs. Importantly, a polymorphism in the XBP1 promoter was suggested as a risk factor to develop AD. Here, we demonstrate a positive correlation between the progression of AD histopathology and the activation of IRE1 in human brain tissue. To define the significance of the UPR to AD, we targeted IRE1 expression in a transgenic mouse model of AD. Despite initial expectations that IRE1 signaling may protect against AD, genetic ablation of the RNase domain of IRE1 in the nervous system significantly reduced amyloid deposition, the content of amyloid β oligomers, and astrocyte activation. IRE1 deficiency fully restored the learning and memory capacity of AD mice, associated with improved synaptic function and improved long-term potentiation (LTP). At the molecular level, IRE1 deletion reduced the expression of amyloid precursor protein (APP) in cortical and hippocampal areas of AD mice. In vitro experiments demonstrated that inhibition of IRE1 downstream signaling reduces APP steady-state levels, associated with its retention at the ER followed by proteasome-mediated degradation. Our findings uncovered an unanticipated role of IRE1 in the pathogenesis of AD, offering a novel target for disease intervention.

The authors cover literature involving biochemical and seeding properties of major ALS-linked proteins including superoxide dismutase 1 (SOD1), transactive response DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS) in different systems including invertebrate and mammalian models. According to the evidence discussed, redox modifications such as S-nitrosylation and ALS-linked mutations in PDIs impair their redox activity, resulting in protein misfolding and disulfide-dependent aggregation. Employing cell culture and transgenic mouse models, the authors show that cytoplasmic TDP-43 impairs the proteostasis network by inhibiting translation, which was monitored by puromycin labeling, in addition to preparation of mRNA-ribosome complexes from brain tissue. According to the authors, multiple mechanisms may be associated to suppression of protein synthesis by TDP-43 that deserve further investigation, including disruption of mRNA recruitment by ribosomes, sequestration of ribosome components into protein inclusions, aberrant formation of stress granules, ER stress and activation of the unfolded protein response, among others.

Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal paralytic disorder associated with motor neuron death. Mutant superoxide dismutase 1 (SOD1) misfolding and aggregation have been linked to familial ALS, with the accumulation of abnormal wild-type SOD1 species being also observed in postmortem tissue of sporadic ALS cases. Both wild-type and mutated SOD1 are reported to contribute to motoneuron cell death. The autophagic pathway has been shown to be dysregulated in ALS. Recent evidence suggests a dual time-dependent role of autophagy in the progression of the disease. PACER, also called RUBCNL (Rubicon-like), is an enhancer of autophagy and has been found diminished in its levels during ALS pathology in mice and humans. Pacer loss of function disturbs the autophagy process and leads to the accumulation of SOD1 aggregates, as well as sensitizes neurons to death. Therefore, here we investigated if constitutive overexpression of PACER in neurons since early development is beneficial in an in vivo model of ALS. We generated a transgenic mouse model overexpressing human PACER in neurons, which then was crossbred with the mutant SOD1 G93A ALS mouse model. Unexpectedly, PACER/SOD1 G93A double transgenic mice exhibited an earlier disease onset and shorter lifespan than did littermate SOD1 G93A mice. The overexpression of PACER in neurons in vivo and in vitro increased the accumulation of SOD1 aggregates, possibly due to impaired autophagy. These results suggest that similar to Pacer loss-of function, Pacer gain-of function is detrimental to autophagy, increases SOD1 aggregation and worsens ALS pathogenesis. In a wider context, our results indicate the requirement to maintain a fine balance of PACER protein levels to sustain proteostasis.

Amyotrophic lateral sclerosis (ALS) is the most frequent paralytic disease in adults. Most ALS cases are considered sporadic with no clear genetic component. The disruption of protein homeostasis due to chronic stress responses at the endoplasmic reticulum (ER) and the accumulation of abnormal protein inclusions are extensively described in ALS mouse models and patient-derived tissue. Recent studies using pharmacological and genetic manipulation of the unfolded protein response (UPR), an adaptive reaction against ER stress, have demonstrated a complex involvement of the pathway in experimental models of ALS. In addition, quantitative changes in ER stress-responsive chaperones in body fluids have been proposed as possible biomarkers to monitor the disease progression. Here we review most recent advances attributing a causal role of ER stress in ALS.

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.

Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease that affects motoneurons. Mutations in superoxide dismutase 1 (SOD1) have been described as a causative genetic factor for ALS. Mice overexpressing ALS-linked mutant SOD1 develop ALS symptoms accompanied by histopathological alterations and protein aggregation. The protein disulfide isomerase family member ERp57 is one of the main up-regulated proteins in tissue of ALS patients and mutant SOD1 mice, whereas point mutations in ERp57 were described as possible risk factors to develop the disease. ERp57 catalyzes disulfide bond formation and isomerization in the endoplasmic reticulum (ER), constituting a central component of protein quality control mechanisms. However, the actual contribution of ERp57 to ALS pathogenesis remained to be defined. Here, we studied the consequences of overexpressing ERp57 in experimental ALS using mutant SOD1 mice. Double transgenic SOD1 G93A /ERp57 WT animals presented delayed deterioration of electrophysiological activity and maintained muscle innervation compared to single transgenic SOD1 G93A littermates at early-symptomatic stage, along with improved motor performance without affecting survival. The overexpression of ERp57 reduced mutant SOD1 aggregation, but only at disease end-stage, dissociating its role as an anti-aggregation factor from the protection of neuromuscular junctions. Instead, proteomic analysis revealed that the neuroprotective effects of ERp57 overexpression correlated with increased levels of synaptic and actin cytoskeleton proteins in the spinal cord. Taken together, our results suggest that ERp57 operates as a disease modifier at early stages by maintaining motoneuron connectivity.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motoneurons and paralysis. The mechanisms underlying neuronal degeneration in ALS are starting to be elucidated, highlighting disturbances in motoneuron proteostasis. Endoplasmic reticulum (ER) stress has emerged as an early pathogenic event underlying motoneuron vulnerability and denervation in ALS. Maintenance of ER proteostasis is controlled by a dynamic signaling network known as the unfolded protein response (UPR). Inositol-requiring enzyme 1 (IRE1) is an ER-located kinase and endoribonuclease that operates as a major ER stress transducer, mediating the establishment of adaptive and pro-apoptotic programs. Here we discuss current evidence supporting the role of ER stress in motoneuron demise in ALS and build the rational to target IRE1 to ameliorate neurodegeneration.

Abnormal modifications to mutant superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (fALS). Misfolding of wild-type SOD1 (SOD1WT) is also observed in postmortem tissue of a subset of sporadic ALS (sALS) cases, but cellular and molecular mechanisms generating abnormal SOD1WT species are unknown. We analyzed aberrant human SOD1WT species over the lifetime of transgenic mice and found the accumulation of disulfide–cross-linked high–molecular-weight SOD1WT aggregates during aging. Subcellular fractionation of spinal cord tissue and protein overexpression in NSC-34 motoneuron-like cells revealed that endoplasmic reticulum (ER) localization favors oxidation and disulfide-dependent aggregation of SOD1WT. We established a pharmacological paradigm of chronic ER stress in vivo,which recapitulated SOD1WT aggregation in young transgenicmice. These species were soluble in nondenaturing detergents and did not react with a SOD1 conformation-specific antibody. Interestingly, SOD1WT aggregation under ER stress correlated with astrocyte activation in the spinal cord of transgenic mice. Finally, the disulfide–cross-linked SOD1WT species were also found augmented in spinal cord tissue of sALS patients, correlating with the presence of ER stress markers. Overall, this study suggests that ER stress increases the susceptibility of SOD1WT to aggregate during aging, operating as a possible risk factor for developing ALS.

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. In this paper, we present a description of the digestive system of N. furzeri, with emphasis on the intestine. We note that the general architecture of the intestinal tissue is shared with other vertebrates, and includes a folding mucosa, an outer muscle layer and a myenteric plexus. By immunohistochemical analysis, we reveal that the mucosa harbours the same type of epithelial cells observed in mammals, including enterocytes, goblet cells and enteroendocrine cells, and that the myenteric neurons express neurotransmitters common to other species, such as serotonin, substance P and tyrosine hydroxylase. In addition, we detect the presence of a proliferative compartment at the base of the intestinal folds. The description of the normal intestinal morphology provided here constitutes a baseline information to contrast with tissue alterations in future lines of research assessing pathologies, ageing-related diseases or damage caused by toxic agents.