Abstract In neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt ...to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a ‘proteostasis network’ and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge – the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson׳s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses and the molecular pathways they recruit might be exploited for therapeutic gain. This article is part of a Special Issue entitled SI:ER stress.
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 (SOD1
and TDP43
) 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.
Tempol has been shown to protect experimental animals from injuries associated with excessive nitric oxide production. In parallel, tempol decreased the levels of protein-3-nitrotyrosine in the ...injured tissues, suggesting that it interacted with nitric oxide-derived oxidants such as nitrogen dioxide and peroxynitrite. Relevantly, a few recent studies have shown that tempol catalytically diverts peroxynitrite/carbon dioxide reactivity toward phenol from nitration to nitrosation. To examine whether this shift occurs in biological environments, we studied the effects of tempol (10–100 μM) on peroxynitrite/carbon dioxide (1 mM/2 mM) reactivity toward proteins, native bovine serum albumin (BSA) (0.5–0.7 cys/mol) and reductively denatured BSA (7–19 cys/mol), and cells (J774 macrophages). Although not a true catalyst, tempol strongly inhibited protein–tyrosine nitration (70–90%) and protein–cysteine oxidation (20–50%) caused by peroxynitrite/carbon dioxide in BSA, denatured BSA, and cells while increasing protein–cysteine nitrosation (200–400%). Tempol consumption was attributed mainly to its reaction with protein–cysteinyl radicals. Most of the tempol, however, reacted with the radicals produced from peroxynitrite/carbon dioxide, that is, nitrogen dioxide and carbonate radical anion. Accordingly, tempol decreased the yields of BSA–cysteinyl and BSA–tyrosyl/tryptophanyl radicals, as well their decay products such as protein–3-nitrotyrosine. The parallel increase in protein–nitrosocysteine yields demonstrated that part of the peroxynitrite is oxidized to nitric oxide by the oxammonium cation produced from tempol oxidation by peroxynitrite/carbon dioxide-derived radicals. Protein–nitrosocysteine formation was shown to occur by radical and nonradical mechanisms in studies with a protein–cysteinyl radical trapper. These studies may contribute to the understanding of the protective effects of tempol in animal models of inflammation.
To determine the effectiveness of a multidisciplinary, outpatient pulmonary rehabilitation (PR) program in patients with severe and very severe chronic obstructive pulmonary disease (COPD). PR is ...recommended in advanced COPD, but there is limited evidence on the effectiveness of PR in reducing health care resources when applied in outpatients.
Before and after intervention, a prospective research trial of patients enrolled in a PR program.
Outpatient respiratory department in a specialized hospital.
We considered prospectively 82 consecutive patients with advanced COPD and finally studied 72 patients who completed the PR intensive phase.
PR program.
The effectiveness of this PR program was assessed by comparing health resources use from the year before and the year after PR. Clinical variables including dyspnea; the body mass index, obstruction, dyspnea, exercise capacity (BODE) index; and the Chronic Respiratory Questionnaire and health resources use including the number of exacerbations, the number of hospitalizations, and days of hospitalization.
Patients had a forced expiratory volume in the first second percentage predicted (mean +/- SD) of 33.0+/-9.8 and a BODE index of 5.0+/-2.0. Significant improvements after PR were found in dyspnea, exercise capacity, and quality of life and on the BODE index (P<.05). Compared with the 12 months before PR, there were also significant reductions during the year after PR on exacerbations (3.4+/-3.5 vs 1.9+/-2.0, P=.002), hospitalizations (2.4+/-2.0 vs 0.9+/-1.2, P<.001), and days of hospitalization (36.1+/-32.7 vs 16.1+/-31.3, P<.001) (ie, a reduction of 44%, 63%, and 55%, respectively; all P<.05).
We conclude that a multidisciplinary, outpatient PR program substantially reduces health resources use in patients with severe and very severe COPD.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron death. A 20% of familial ALS cases are associated with mutations in the gene coding for superoxide ...dismutase 1 (SOD1). The accumulation of abnormal aggregates of different proteins is a common feature in motor neurons of patients and transgenic ALS mice models, which are thought to contribute to disease pathogenesis. Developmental morphogens, such as the Wnt family, regulate numerous features of neuronal physiology in the adult brain and have been implicated in neurodegeneration. β-catenin is a central mediator of both, Wnt signaling activity and cell-cell interactions. We previously reported that the expression of mutant SOD1 in the NSC34 motor neuron cell line decreases basal Wnt pathway activity, which correlates with cytosolic β-catenin accumulation and impaired neuronal differentiation. In this work, we aimed a deeper characterization of β-catenin distribution in models of ALS motor neurons. We observed extensive accumulation of β-catenin supramolecular structures in motor neuron somas of pre-symptomatic mutant SOD1 mice. In cell-cell appositional zones of NSC34 cells expressing mutant SOD1, β-catenin displays a reduced co-distribution with E-cadherin accompanied by an increased association with the gap junction protein Connexin-43; these findings correlate with impaired intercellular adhesion and exacerbated cell coupling. Remarkably, pharmacological inhibition of the glycogen synthase kinase-3β (GSK3β) in both NSC34 cell lines reverted both, β-catenin aggregation and the adverse effects of mutant SOD1 expression on neuronal differentiation. Our findings suggest that early defects in β-catenin distribution could be an underlying factor affecting the onset of neurodegeneration in familial ALS.
•β-catenin accumulates in macromolecular structures in models of ALS motor neurons.•β-catenin dissociates from cell-cell contacts and associates to gap junctions in NSC34-hSOD1G93A cells.•NSC34-hSOD1G93A cells display impaired intercellular adhesion and increased cell coupling.•GSK3β inhibition reverts β-catenin accumulation and rescues neuronal differentiation of ALS-like cells.
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