Recent studies suggest that the toxicity of familial amyotrophic lateral sclerosis mutant Cu, Zn superoxide dismutase (SOD1) arises from its selective recruitment to mitochondria. Here we demonstrate that each of 12 different familial ALS-mutant SOD1s with widely differing biophysical properties are associated with mitochondria of motoneuronal cells to a much greater extent than wild-type SOD1, and that this effect may depend on the oxidation of Cys residues. We demonstrate further that mutant SOD1 proteins associated with the mitochondria tend to form cross-linked oligomers and that their presence causes a shift in the redox state of these organelles and results in impairment of respiratory complexes. The observation that such a diverse set of mutant SOD1 proteins behave so similarly in mitochondria of motoneuronal cells and so differently from wild-type SOD1 suggests that this behavior may explain the toxicity of ALS-mutant SOD1 proteins, which causes motor neurons to die. motor neuron ͉ neurodegeneration ͉ amyotrophic lateral sclerosis I n the familial form of ALS (fALS), which is linked to mutations in the Cu, Zn superoxide dismutase (SOD1) gene, it is generally considered that the pathological phenotype is because of the acquisition by the mutant SOD1 protein of new properties that transform it from a highly stable, dimeric antioxidant enzyme into a protein with a propensity to form toxic aggregates and cause oxidative damage to neuronal tissue (1). More than 100 different ALS-causing mutations in the SOD1 gene have been reported to date, and the properties of many of the fALS-linked mutant SOD1 proteins (mutSOD1s) have been studied (2-8) in a concerted effort to identify properties common to the mutant proteins but not shared by wild-type SOD1 (wtSOD1), which might explain their toxicity. Instead of similarities, however, biochemical and biophysical studies of the mutSOD1s have revealed a wide range of differences; in fact, some of the mutSOD1s have been found to be very similar to wtSOD1 in all of the properties that have been measured (1). For example, mutSOD1s with substitutions at or near the metalbinding region have altered metal-binding properties and a tendency to crystallize in filamentous structures, but other mutSOD1s with substitutions remote from the metal-binding region are very similar to wtSOD1 in their crystal structures (9-11). Likewise, the global stabilities of some of the metal ion-free mutSOD1 apoproteins are severely compromised, but others have apoproteins that are nearly identical to or even more stable than apo-wtSOD1 (7). Therefore, other abnormal properties of the mutant proteins must be sought to explain the toxicity of all of the mutSOD1s.We reasoned that the common properties shared by the ALS-mutSOD1 proteins and not by wtSOD1 protein might only become apparent when the mutant proteins were studied within the cellular context and also, possibly, only within motoneuronal cells. We have therefore built a collection of inducible cell lines, derived from a mouse motoneuronal line...

Background/purpose of the studyEpidemiological evidence suggests that low doses of ionising radiation (≤1.0 Gy) produce persistent alterations in cognition if the exposure occurs at a young age. The mechanisms underlying such alterations are unknown. We investigated the long-term effects of low doses of total body gamma radiation on neonatally exposed NMRI mice on the molecular and cellular level to elucidate neurodegeneration.ResultsSignificant alterations in spontaneous behaviour were observed at 2 and 4 months following a single 0.5 or 1.0 Gy exposure. Alterations in the brain proteome, transcriptome, and several miRNAs were analysed 6–7 months post-irradiation in the hippocampus, dentate gyrus (DG) and cortex. Signalling pathways related to synaptic actin remodelling such as the Rac1-Cofilin pathway were altered in the cortex and hippocampus. Further, synaptic proteins MAP-2 and PSD-95 were increased in the DG and hippocampus (1.0 Gy). The expression of synaptic plasticity genes Arc, c-Fos and CREB was persistently reduced at 1.0 Gy in the hippocampus and cortex. These changes were coupled to epigenetic modulation via increased levels of microRNAs (miR-132/miR-212, miR-134). Astrogliosis, activation of insulin-growth factor/insulin signalling and increased level of microglial cytokine TNFα indicated radiation-induced neuroinflammation. In addition, adult neurogenesis within the DG was persistently negatively affected after irradiation, particularly at 1.0 Gy.ConclusionThese data suggest that neurocognitive disorders may be induced in adults when exposed at a young age to low and moderate cranial doses of radiation. This raises concerns about radiation safety standards and regulatory practices.Electronic supplementary materialThe online version of this article (doi:10.1186/1750-1326-9-57) contains supplementary material, which is available to authorized users.

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Motor neuron death in amyotrophic lateral sclerosis (ALS) is considered a “non-cell autonomous” process, with astrocytes playing a critical role in disease progression. Glial cells are activated early in transgenic mice expressing mutant SOD1, suggesting that neuroinflammation has a relevant role in the cascade of events that trigger the death of motor neurons. An inflammatory cascade including COX2 expression, secretion of cytokines and release of NO from astrocytes may descend from activation of a NF-κB-mediated pathway observed in astrocytes from ALS patients and in experimental models. We have attempted rescue of transgenic mutant SOD1 mice through the inhibition of the NF-κB pathway selectively in astrocytes. Here we show that despite efficient inhibition of this major pathway, double transgenic mice expressing the mutant SOD1G93A ubiquitously and the dominant negative form of IκBα (IκBαAA) in astrocytes under control of the GFAP promoter show no benefit in terms of onset and progression of disease. Our data indicate that motor neuron death in ALS cannot be prevented by inhibition of a single inflammatory pathway because alternative pathways are activated in the presence of a persistent toxic stimulus.

Therapeutic irradiation of pediatric and adult patients can profoundly affect adult neurogenesis, and cognitive impairment manifests as a deficit in hippocampal-dependent functions. Age plays a major role in susceptibility to radiation, and younger children are at higher risk of cognitive decay when compared to adults. Cranial irradiation affects hippocampal neurogenesis by induction of DNA damage in neural progenitors, through the disruption of the neurogenic microenvironment, and defective integration of newborn neurons into the neuronal network. Our goal here was to assess cellular and molecular alterations induced by cranial X-ray exposure to low/moderate doses (0.1 and 2 Gy) in the hippocampus of mice irradiated at the postnatal ages of day 10 or week 10, as well as the dependency of these phenomena on age at irradiation. To this aim, changes in the cellular composition of the dentate gyrus, mitochondrial functionality, proteomic profile in the hippocampus, as well as cognitive performance were evaluated by a multidisciplinary approach. Our results suggest the induction of specific alterations in hippocampal neurogenesis, microvascular density and mitochondrial functions, depending on age at irradiation. A better understanding of how irradiation impairs hippocampal neurogenesis at low and moderate doses is crucial to minimize adverse effects of therapeutic irradiation, contributing also to radiation safety regulations.