1A) A modest increase in the absolute numbers of Tconv cells was

1A). A modest increase in the absolute numbers of Tconv cells was also seen (Fig. 1D). A similar enhancement in Treg cells was seen in mice treated with a different preparation of Fc-GITR-L [13], but these authors did not observe any increase in Tconv cells. To determine if GITR stimulation modulated Treg-cell function, we purified CD4+CD25+T cells from Fc-GITR-L and IgG1-injected mice and assessed their suppressive capacity in vitro (Supporting Information Fig. 1B). Treg cells from Fc-GITR-L-treated

mice were as suppressive as Treg cells from control human IgG1-treated mice. The increase in Treg cells was transient and the percentage of Foxp3+ T cells returned to normal by day 9 after treatment (Supporting Information Fig. DAPT in vivo 1C). Previous studies suggested that treatment of mice with an agonist anti-GITR mAb, following anti-CD25 depletion of Treg cells, was capable of enhancing the pathogenicity of autoantigen-specific T cells in an experimental autoimmune encephalomyelitis model [18]. One problem with this approach is that Treg-cell depletion is usually incomplete and Treg cells rapidly

repopulate the treated animals [19]. To more directly address the effects of GITR stimulation on Teff cell numbers and function, we used the IBD model [20] and transferred CD4+CD45RBhi Foxp3− T cells into RAG KO mice p38 kinase assay followed by weekly treatment with Fc-GITR-L (100 μg/mouse i.v.). Mice treated with Fc-GITR-L exhibited a markedly enhanced loss of weight compared with mice that just received CD4+CD45RBhi T cells (Fig. 2A). The percentage of CD4+ T cells secreting IFN-γ was similar in treated and control animals (Fig. 2B and D), but the absolute number of CD4+ T cells secreting IFN-γ was markedly increased in the mesenteric LN (Fig. 2C). In contrast, we observed no changes in either the percentages or absolute numbers of IL-17-producing T cells (Fig. 2E and F).

Teff-cell expansion was also reflected in enhanced Ki67 staining in the treated mice (Fig. 2G and H). Thus, engagement of the GITR by GITR-L in vivo has no effect on T-cell differentiation, but significantly augments the absolute number of pathogenic IFN-γ producing T cells and disease severity. Our results are similar to the effects of Flavopiridol (Alvocidib) GITR engagement that have been reported [21] on CD8+ Teff cells in a viral model where GITR engagement increased CD8+ T-cell expansion without enhancing their effector functions. Small percentages of Foxp3+ iTreg cells were observed in mice that received CD4+CD45RBhi Foxp3− T cells, but the percentages were the same in untreated or GITR-L-treated mice (data not shown). The GITR is also expressed on APCs and NK cells at a low levels [2] and it has been suggested [22, 23] that some of the effects of GITR engagement in vivo may be secondary to modulation of innate immune functions. To address this issue, we transferred CD4+CD45RBhi T cells from GITR−/− mice to RAG−/− mice (Supporting Information Fig. 2A).

As with other types of myofibrillar myopathies [28,29], the typic

As with other types of myofibrillar myopathies [28,29], the typical light microscopy features of Chinese desminopathy patients included: (i) abnormal fibre regions harbouring amorphous materials, nemaline-like structures, and cytoplasmic bodies in MGT-stained sections. We found that amorphous materials were more common than other changes; (ii) sharply abnormal regions with a decrease in oxidative enzyme activity including core and rubbed-out fibres; (iii) rimmed vacuoles; and (iv) ectopic aggregations of desmin and other

proteins. However, our observations illustrated the broad variability in myopathological changes from patient to patient. A relationship between pathological changes and mutation positions in the desmin gene could not be established, even in GPCR Compound Library order individuals from the same family. In two related Dutch families with the S13F mutation in the head domain, muscle biopsies showed dystrophic changes in three patients and mild myopathic changes in the other one. All presented with no occurrence of amorphous materials in the fibres [28]. In our observations, the index case of the S12F mutation of the head domain had a dystrophy-like change with amorphous material in the selleck chemicals llc abnormal fibres, while his elder brother

showed myopathy-like changes with numerous cytoplasmic bodies which has been described by Pica et al. in a Chinese patient with the S13F mutation [22]. Most rod domain mutations were reported to show amorphous accumulations in abnormal fibre regions in MGT staining [6]. However, we 2-hydroxyphytanoyl-CoA lyase found that amorphous materials were also dominant in patients with mutations in the tail domain. Our observations suggest that it is difficult to predict the mutation positions in the desmin

gene from the different light microscopy features. Electron microscopy plays a central role in the diagnostic workup of myofibrillar myopathy. Most reports have emphasized that granulofilamentous electron-dense materials between myofibrils or in subsarcolemmal areas are ultrastructural features of desminopathy [30], and these were identified in all our patients. Other ultrastructural features included cytoplasmic bodies, nemaline bodies, and ‘ring like structures’[22,31,32]. We could not find any differences between desminopathy and filaminopathy, resulting from defects in the filamin c gene, in the cytoplasmic bodies in electron microscopy [33]. The ‘ring-like structure’, a phenomenon firstly described by Pruszczyk et al. in a patient with the E413K mutation in the tail domain, was similar to granular electron dense material originating from the level of the Z-disc [32]. The ‘ring-like structure’ consists of highly electron-dense materials with a hole in the centre. We found both typical nemaline bodies and ‘ring-like structures’ in two of our patients with a mutation in the rod domain. As the ‘ring-like structure’ was only observed in desminopathy, this pathological change may be another useful indicator in the genetic analysis of the desmin gene.

ucsc edu/cgi-bin/hgGateway) with selected tracks from ENCODE [20]

ucsc.edu/cgi-bin/hgGateway) with selected tracks from ENCODE [20] and GEO databases (naïve CD4+ and Th1 cells: GSE26550, [21]; BMDM: GSE33802 [22]. (B) Analysis of relative resistance to MNase. Data normalized to control MNase-digested genomic DNA and b-actin are shown as mean ± SD of two experiments. Figure S8. Methylation status of TNF promoter in mouse T cells and bone marrow-derived macrophages DNA was isolated from mouse ES cells, embryonic fibroblasts (MEF),

BMDM and various T cells, demethylated by Imprint DNA Modification Kit (Sigma-Aldrich) according to the manufacturer’s instructions and used as template for PCR with primers for amplification of the proximal (forward TGGGTTAGTGAGTGAAAGGGATA, reverse AAATTTCAATTCTCAAAATCCTATACA) and distal (forward GGAATGAATTTAGTTTTGGGAATT, reverse AAATAAACTAAAAAAATCCATCCAAA) parts of mouse TNF promoter. Amplified DNA fragments, click here corresponding to proximal (CpG sites from -255 to +7) and distal (CpG sites from -849 to -670) TNF promoter regions were cloned to TOPO TA Cloning® Kit for Sequencing

(Invitrogen, Carlsbad, CA, USA) and sequenced with BigDye® Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, Austin, TX, USA). From two to nine individual clones were analyzed. Stimulated cells were treated 3 hours with 4 μg/ml of anti-CD3 and 1 μg/ml of anti-CD28 antibodies (αCD3/αCD28) or 10 ng/ml of PMA and 1 μg/ml of Ionomycin (P/I). Figure S9. Binding of NFkB family members to the regulatory elements of the TNF/LT

SP600125 locus in bone marrow derived macrophages (BMDM) and dendritic Y-27632 2HCl cells (BMDC) ChIP-Seq analysis of mouse bone-marrow derived macrophages (GSE16723 [23]) (A) and dendritic cells (GSE36099 [24]) (B) Figure S10. Control of efficiency of T cell polarization T cells were isolated and polarized as described in Materials and Methods and Supporting Information Table 4. Th0s, Th2s and Th17s cells were polarized in the presence of soluble anti-CD3 antibodies; Th0i, Th1i and Th2i cells were polarized in the presence of immobilized anti-CD3 antibodies. Cells were stimulated by 10 ng/ml PMA and 1 μg/ml Ionomycin for 4 hours in the presence of 5 μg/ml of Brefeldin A and fixed for at least 30 min with 2% paraformaldehyde in PBS. Further washing and staining steps were performed in PBS/BSA/EDTA buffer supplemented with 0.5% Saponin. Cells were analyzed on a FACSCalibur, FACS-Canto or Fortessa (BD Biosciences, Franklin Lakes, NJ, USA) flow cytometers using CellQuest (BD Biosciences) and FlowJo 7.6 (Tree Star, Inc., Ashland, OR, USA) software. Data shown are representative of five experiments. “
“The type III secretion system (T3SS) plays a key role in the exertion of full virulence by Bordetella bronchiseptica. However, little is known about the environmental stimuli that induce expression of T3SS genes.

caninum antigens

were not indicative for protection (10,4

caninum antigens

were not indicative for protection (10,41,45). selleck inhibitor Assessment of i.n. vaccinated animals confirmed the earlier findings on the protection achieved with recNcPDI (19). Of course, one problem with i.n. vaccination is the restricted amount of antigen which can be administered to mice. Nevertheless, i.n vaccination of mice with the 1 μg recNcPDI antigen conferred protection against cerebral disease (90%), together with low cerebral parasite burden. Association of recNcPDI with the chitosan/alginate or chitosan/alginate-mannose nanogels may have increased this efficacy – with the antigen associated with chitosan/alginate nanogels, 100% of the mice were protected – however, the high number of protected mice with the antigen in the absence of nanogels precluded a clear indication that the nanogels had an added value. It would be necessary to perform additional studies, in which the antigen load per vaccination was titrated, to see whether the limit of inducing protective antibody is lower with nanogel-associated antigen. Nevertheless, the present work demonstrates that nanogel-associated antigen is indeed an efficacious vaccine, and the results from the i.p. vaccination suggest that the nanogels are providing an

added value to the vaccine efficacy. Moreover, quantification of cerebral infection intensities in i.n. vaccinated animals showed that nanogel delivery of the vaccine had an advantage over the nanogel-free vaccine. Although the chitosan/alginate nanogel-associated antigen appeared to be more efficacious than chitosan/alginate-mannose Rucaparib purchase nanogel-associated antigen in limiting cerebral infection compared, the differences were only slight. Others have shown that protective immune responses against experimentally induced neosporosis in acute disease mouse models have been mainly associated with the development of a Th1-type immune response, dominated by IgG2a antibody production and natural killer (NK) cell proliferation with increased IFN-γ production Tideglusib (51,52).

However, there are also reports on protective effects achieved by Th2-type responses in acute disease (40,42–44) and in foetal infection models (44). All these observations support the idea that both Th1 and Th2-driven immune mechanisms can limit disease, at least in the mouse model. Indeed, our own results are showing the presence of a mixed Th1/Th2 response induced in nanogel-delivered vaccine immunized mice, protected from disease, and showing reduced cerebral parasite load. To elaborate on the type of immune response (Th1 or Th2) induced, we analysed the level of cytokine mRNA transcription in splenic tissue. It is important to note that the cytokine pattern described is the combined result of immune responses to both vaccination and infection.

The majority of patients (93 0%) were waiting for kidney transpla

The majority of patients (93.0%) were waiting for kidney transplantation. More than half of the respondents (63.3%) had been waiting Omipalisib for more than 3 years. Patients with longer transplant waiting times had lower self-estimated chance of receiving a transplant (P = 0.004). Self-estimated chance of getting transplanted

was positively associated with the happiness score (P < 0.0001). Issues of most concerns to the patients waiting for organ transplants were: inconvenience of therapy (48.2%), disease progression (47.9%), burden to family (59.5%) and financial difficulties (52.3%). More female patients on the waiting list (50.0% vs 25.7% in male) reported concerns about suffering associated with the illnesses. 21.7% of patients considered

the level of support received inadequate. Conclusions:  Our patients had long waiting time for transplantation, which is associated with a lower perceived chance of getting a transplant. Attention to more psychosocial support to these patients waiting for organ transplant is important. Promoting and improving organ donation would be the ultimate way to help these patients. “
“Aim:  The prognosis for HIV patients needing acute dialysis is uncertain. The aim of this study was to describe the clinical presentation, renal diagnoses and outcomes of HIV patients who underwent acute haemodialysis at Groote Schuur Hospital in the period 2002–2007. Methods:  A retrospective review of case records of HIV patients who underwent acute haemodialysis was conducted. Results:  SP600125 Y-27632 2HCl One hundred and seventeen patients were reviewed (median age 34.0 years (29.0–40.0) 53.8% men, 93.2% black Africans) and 33 had a renal biopsy. Acute tubular necrosis (ATN) was diagnosed in 68 patients. Recovery of renal

function occurred in 33.3% of all patients while in 25.7% treatment was withdrawn and 41.0% died in hospital. Suspected ATN was the commonest cause of renal disease in those who recovered renal function (82.1%). A higher CD4 count (odds ratio (OR) = 0.994, P = 0.007), lower pre-dialysis serum creatinine (<1230 µmol/L) and longer hospitalization (OR = 0.93, P = 0.006) significantly correlated with survival. Conclusion:  There is a good chance of survival for HIV patients needing acute dialysis when the diagnosis is ATN, and when the CD4 count is more than 200 cells/mm3. "
“While darbepoetin alfa (DA) can be administered once monthly (QM) to maintain haemoglobin (Hb) concentrations in anaemic patients with chronic kidney disease not on dialysis (CKD-ND), the QM use of DA for anaemia correction has not been previously investigated. In this randomized, double-blind, non-inferiority, active-controlled study, adult subjects with CKD-ND, Hb levels <10 g/dL, and not treated with an erythropoiesis-stimulating agent were randomized 1:1 to receive DA every 2 weeks (Q2W) or QM for 33 weeks with initial doses of 0.75 μg/kg Q2W or 1.5 μg/kg QM.

The data indicate that LPG and L mexicana parasites exert opposi

The data indicate that LPG and L. mexicana parasites exert opposing effects on PKCα activity of susceptible and resistant mouse macrophages, which correlate with the magnitude of burst oxidation and with the survival of the parasites within macrophages. Taken together, our data suggest that PKCα plays an important role in the L. mexicana infection outcome in vitro. One of the primary defence mechanisms of macrophages against Leishmania infections is the oxidative metabolism. It has been shown that L. donovani PD0325901 nmr parasites avoid triggering the oxidative burst by actively inhibiting

PKC in macrophages (30), and the molecule responsible of this inhibition is LPG (20). LPG is a

glycosylinositolphospholipid (GPI)-anchored polymer formed by repeating disaccharide-phosphate units, through which promastigotes interact with both the insect vector and the mammalian host. LPG is essential for infecting macrophages through various mechanisms. It has been shown that LPG alters the organization of lipid microdomains on the phagosome membrane. Additionally, LPG participates in other immune evasion mechanisms such as the efficient of scavenging toxic oxygen metabolites, modulation of inducible nitric oxide synthase (iNOS) and downregulation of PKC activation, required for the assembly of the NADPH oxidase complex (31,32). It has been proposed that STA-9090 nmr a fraction of LPG intercolates from the lipid bilayer of the parasite to the lipid bilayer of the macrophage (33). PKCα, which is rapidly recruited to the nascent phagosome, is the predominant isoenzyme required for the O2− production and additionally regulates other macrophage functions related to host defence, such as FcγR-mediated phagocytosis and signal transduction leading to activation of ERK1/2 (14,34,35). PKCα is associated with the phagosomal membrane and phosphorylates the

myristoylated alanine-rich C kinase substrate (MARCKS), Interleukin-3 receptor a membrane protein associated with actin-based motility and with membrane trafficking. PKC-dependent phosphorylation of phagosome MARCKS leads to the movement of both lysosomes and phagosomes on microtubules, that is required for their interaction. In the J774 cell line, it has been demonstrated that the inhibition of PKCα by L. donovani LPG leads to the inhibition of F-actin depolymerization at the phagosomal membrane, thereby avoiding the fusion events required for the delivery of endosomal contents into parasitophorous vacuoles, thus permitting parasite multiplication (35–37). In this work, we analysed if the modulation of PKCα by LPG of L. mexicana was related to parasite survival in macrophages of susceptible BALB/c mice vs. cells of the more resistant C57BL/6 mice. We found that L.

Antibodies against S cerevisiae

have been shown to be di

Antibodies against S. cerevisiae

have been shown to be disease marker for Crohn’s disease (CD) [151], possibly indicating that fungi could play a role in the aberrant immune responses in IBD [152]. A few studies have been conducted to examine fungal community dysbiosis in chronic disease, including that in IBD [16, 153]. Fungal diversity in the large intestine of patients with CD is higher than that seen in healthy subjects [16]. The study of the mycobiome in a murine model of induced colitis highlighted MK-8669 the importance of the gut mycobiota in contributing to the boost in intestinal inflammation seen upon dextran sodium sulfate (DSS) treatment [152], with a marked increase in the abundance of C. tropicalis observed during active colitis. These studies are the first steps toward clarifying the role of the gut mycobiota MAPK inhibitor in intestinal inflammation, and may help explain the increased serum levels of anti-S. cerevisiae antibodies in CD patients [151]. A number of other opportunistic infections are generally ascribed to defective host immunity but may require specific

microbial population dysbiosis [153]. Longitudinal molecular typing studies indicate that disseminated C. albicans infections originate from an individual’s own commensal strains [154], and the transition to virulence is generally thought to reflect impaired host immunity. However, recent data indicate

that the ability of a commensal organism to produce disease is not merely a consequence of impaired host immunity. Suzanne Noble and colleagues [155] showed that the opportunistic pathogen C. albicans can enter a specific, regulated commensal state called GUT (gastrointestinally induced transition) in the host intestine. Candida albicans in the GUT state have a unique phenotype that promotes carriage in the gut in Clomifene a benign state, in which virulence-associated genes, such as the white-opaque switching and hyphal formation genes, are downregulated, enabling fungal adaptation for long-term survival in the large intestine [155]. Nevertheless, GUT cells can promote pathogenesis when host immunity is impaired. These new findings suggest that more attention will be directed toward understanding fungal persistence, colonization, and commensalisms — processes that may have evolved over many thousands of years of coevolution within the human host. Diet is a constant and dynamic factor shaping mucosal immunity as well as the composition of resident microbial populations in the gut. To maintain gut homeostasis, immune cells must sample Ags from the intestinal lumen and deliver them to lymph nodes for presentation to T cells (Fig. 1). In the lymph nodes, CX3CR1+ macrophages and CD103+ DCs collaborate in a fascinating way to capture soluble food Ags [156] and induce oral tolerance.

6) Therefore, IL-21 may achieve its effect by activating target

6). Therefore, IL-21 may achieve its effect by activating target genes downstream of STAT1, this website STAT3 and STAT5 in the activated naive CD8+ T cells. Interleukin-21 is a pleiotropic cytokine that has a broad range

of activations on immune cells. The effect of IL-21 on the differentiation of Th subsets is beginning to be delineated. In vitro stimulation of naive CD4+ T cells under Th1- or Th2-polarized conditions showed no differences in the levels of IFN-γ or IL-4 in normal and IL-21R knockout mice,15 suggesting that IL-21 has no effects on the differentiation of Th1 and Th2 cells in mice. However, IL-17 production was significantly lower in CD4+ T cells from IL-21R knockout mice than in those from normal mice under Th17-polarized conditions, demonstrating that IL-21 exerts critical functions in Th17 cell development.3,7 Two recent papers have described an IL-22-producing helper T cell population that co-expresses the chemokine receptor CCR6 and the skin-homing receptors CCR4 and CCR10.16,17 These

cells are distinct from both Th17 cells and Th1 cells. However, the effect of IL-21 on the differentiation of IL-22-producing T cells is not clear. It has been shown that IL-21 up-regulates the expression of IL-22 mRNA in activated naive CD4+ T cells.3 Consistent with these results, we found that IL-21 induced see more IL-22 production in activated naive CD4+ T cells at protein level. Unexpectedly, we demonstrated that IL-21 also induced IL-22 production in activated naive CD8+ T cells and the frequency of IL-22-producing cells in CD8+ T cells was higher than in CD4+ T cells from CBMCs. Moreover, IL-21 did

not induce IL-17 production in CD8+ T cells. These data suggest that there are some differences between the induction of IL-22 and IL-17. A transcription factor that might be involved in IL-22 expression is the aryl hydrocarbon receptor. The aryl hydrocarbon receptor agonist substantially alters the balance of IL-22 versus IL-17-producing cells.16 In line with previous studies showing that TGF-β, Adenosine triphosphate the critical factor in the development of Th17 cells, inhibited IL-22 production in CD4+ T cells,3 we showed that the addition of TGF-β inhibited the production of IL-22 but induced IL-17 production in activated naive CD8+ T cells. Our results demonstrated that, compared with IL-23 (data not shown), IL-21 induced higher levels of IL-22 in activated naive CD8+ T cells. Interleukin-21 belongs to the common γc-signalling cytokine family that includes IL-2, IL-7 and IL-15. Here, we found that IL-21 but not IL-15 or IL-2 induced the differentiation of Tc22 cells by naive CD8+ T cells, clearly indicating that signals mediated by the common γc are not specific to enhance IL-22 production. We found that IL-21 induced IL-22 production in naive and memory CD8+ T cells. However, naive CD8+ T cells stimulated with IL-21 produced IL-22 production in greater folds than memory CD8+ T cells.

Although MASP-3 has been reported to have an enzymatic activity t

Although MASP-3 has been reported to have an enzymatic activity towards insulin-like growth factor-binding protein-5, the functional activity of MASP-3 and MAp44 has so far been ascribed primarily to an inhibitory activity on the activation of Doxorubicin the lectin pathway [10], although very recently an activity of MASP-3 in accelerating cleavage of factor B and factor D has been presented [14]. Conversely, MASP-1 is clearly an active enzyme which may initiate cleavage of several substrates, some being members of the complement system but others belonging more traditionally to other physiological systems, i.e. a thrombin-like activity

in cleaving fibrinogen and factor XIII and the protease activated receptor 4 (PAR4) [13,15,16]. Also of note, the MASP1 gene has been implicated in the aetiology STA-9090 cost of the 3MC syndrome, although the mechanism remains unknown [17,18]. An assay for MASP-1 will thus be of importance in a number of scientific fields. The role of MBL was discovered through the study of patients with unexplained susceptibility to infections and opsonin deficiency, as such patients were found to be MBL-deficient [19]. Previously we have described a patient lacking MASP-2, and thus

a functional lectin pathway [20]. It seems plausible that elucidating the role(s) of the MASPs as well as those of the MBL-associated small, non-enzymatic splice products, MAp44 and MAp19 [11,21] may well benefit from epidemiological investigations

on selected patient populations. We thus decided to construct assays for these components. We have presented assays previously for MASP-2, MASP-3, MAp44 and MAp19 [11,21,22]. Similarly, we have generated assays Thalidomide for the recognition molecules associating with the MASPs/MBL-associated proteins (Maps), i.e. MBL, H-, L- [23] and M-ficolin [24]. The development of the assay for MASP-1 presented here was hampered by the difficulty in raising selective monoclonal antibodies (mAb) due to the extensive sharing of domains between the proteins of the MASP1 gene, which encodes three alternative splice products giving rise to the three proteins MASP-1, MASP-3 and MAp44 [25]. MASP-1 and MASP-3 share five domains (constituting the so-called A-chain), whereas they have unique protease domains (SP domains or B-chains), and the protein MAp44 shares its first four domains with MASP-1 and MASP-3 but has an additional 17 unique amino acid residues C-terminally. We have now developed specific anti-MASP-1 antibodies and present here a microtitre well-based inhibition assay which is used for the estimation of some basic parameters as a foundation for future clinical investigations. This, in turn, allows us to explore the relative abundances of the MASPs/MAps and the soluble pattern recognition molecules (PRMs) and hence the physiological equilibrium between these.

The disease clinically presents with lower motor neurone signs of

The disease clinically presents with lower motor neurone signs of progressive weakening and wasting of the voluntary muscles, and upper motor neurone signs of spasticity and hyper-reflexia, with death usually resulting from respiratory failure within 3–5 years of onset [44–46]. At a cytopathological level, mitochondrial dysmorphology is noticeably present, with swollen and vacuolated mitochondria populating motor neurones, muscles and intramuscular nerves [47–49]. Additionally, axonal accumulation of phosphorylated

neurofilaments and somatic formation of ubiquitin-immunoreactive proteinaceous and TAR DNA binding protein-43 (TDP-43) inclusions are all seen in degenerating motor this website neurones [44,46,50,51]. Despite many years of intense research, the aetiology of the disease remains largely ambiguous, with

the majority of cases being sporadic. Several pathogenic processes have been implicated as being causal or contributory to the disease, including oxidative stress, defective axonal transport, glutamatergic excitotoxicity, proteasome see more dysfunction, mitochondrial dysfunction and aberrant functioning of surrounding glial cells (reviewed by [52]). In up to 10% of cases, ALS has a familial origin; mutations in several genes have been identified and implicated in the pathogenesis of the disease. However, both clinically and pathologically, familial and sporadic forms of ALS are usually indistinguishable, leading to speculation that similar pathogenic processes are responsible for both forms of the disease [44,53]. In support of this, mutations in some genes cause or contribute to both familial and sporadic forms of ALS [44,46,52]. Twenty per cent of all familial cases of ALS are caused by autosomal dominant mutations in the gene encoding superoxide dismutase 1 (SOD1) [54]. This ubiquitous enzyme mediates the conversion of a superoxide

anion, derived from oxidative phosphorylation, into hydrogen peroxide, an imperative role in antioxidant defence. However, there is no correlation between SOD1 enzymatic activity and disease onset [46,55]. mTOR inhibitor It has been proposed that ALS results from a toxic gain of function of mutant SOD1 (mSOD1) [46]. Most of the current knowledge concerning the pathogenic process of familial ALS (FALS) in vivo has derived from studies of transgenic mouse models, expressing a number of different SOD1 mutations (reviewed by [53]). Furthermore, as human pathology is almost indistinguishable between sporadic ALS (SALS) and FALS, this mSOD1 mouse model is also used to understand the pathogenesis of SALS. Mitochondria are central to the aetiology of ALS and correlate with mitochondrial involvement in several other neurodegenerative disorders [18,45].