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Reticulon-4A (Nogo-A) Redistributes Protein Disulfide Isomerase to Protect Mice from SOD1-Dependent Amyotrophic Lateral Sclerosis

Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT 06510, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 11/2009; 29(44):13850-9. DOI: 10.1523/JNEUROSCI.2312-09.2009
Source: PubMed

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease inherited in a small subset of patients. The SOD1(G93A) transgenic mouse models this subset of patients, and studies of this strain have suggested that endoplasmic reticulum (ER) stress and deficits in ER chaperone function are contributors to ALS pathophysiology. Here, we demonstrate that the reticulon family of proteins is a novel regulator of the ER chaperone protein disulfide isomerase (PDI), and that through PDI, reticulon-4A (Nogo-A) can protect mice against the neurodegeneration that characterizes ALS. We show that overexpressing reticulon protein induces a punctate redistribution of PDI intracellularly, both in vitro and in vivo. Conversely, reduction of endogenous NogoA expression causes a more homogeneous expression pattern in vivo. These effects occur without induction of the unfolded protein response. To examine the effect of PDI redistribution on ALS disease progression, we conducted survival and behavior studies of SOD1(G93A) mice. Deletion of a single copy of the NogoA,B gene accelerates disease onset and progression, while deletion of both copies further worsens disease. We conclude that NogoA contributes to the proper function of the ER resident chaperone PDI, and is protective against ALS-like neurodegeneration. Our results provide a novel intracellular role for reticulon proteins and support the hypothesis that modulation of PDI function is a potential therapeutic approach to ALS.

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    • "For instance, a link between the early overexpression of RTN4A in ALS muscle fibers was found and consisted in an impairment of the neuromuscular junction, ultimately leading to motor neuron degeneration (Jokic et al. 2006). Additionally, RTN4A was protected from SOD1-dependent ASL by contributing to the correct functioning of the ER (Yang et al. 2009). Conversely, several reports indicate that RTN4A expression is not unique to this disorder (Wojcik et al. 2006; Pradat et al. 2007; Harel et al. 2009; Askanas et al. 2007). "
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    ABSTRACT: Reticulons (RTNs) are a group of membrane-associated proteins mainly responsible for shaping the tubular endoplasmic reticulum network, membrane trafficking, inhibition of axonal growth, and apoptosis. These proteins share a common sequence feature, the reticulon homology domain, which consists of paired hydrophobic stretches that are believed to induce membrane curvature by acting as a wedge in bilayer membranes. RTNs are ubiquitously expressed in all tissues, but each RTN member exhibits a unique expression pattern that prefers certain tissues or even cell types. Recently, accumulated evidence has suggested additional and unexpected roles for RTNs, including those on DNA binding, autophagy, and several inflammatory-related functions. These manifold actions of RTNs account for their ever-growing recognition of their involvement in neurodegenerative diseases like Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, as well as hereditary spastic paraplegia. This review summarizes the latest discoveries on RTNs in human pathophysiology, and the engagement of these in neurodegeneration, along with the implications of these findings for a better understanding of the molecular events triggered by RTNs and their potential exploitation as next-generation therapeutics.
    Neuromolecular medicine 11/2013; 16(1). DOI:10.1007/s12017-013-8271-9
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    • "P values and hazard ratio values are given for each comparison. further supported by the effect of deletion of a PDI regulator, reticulon-4A, which accelerates motor neuron degeneration in the SOD1 transgenic mouse [28]. "
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    ABSTRACT: Protein disulphide isomerase (PDI) plays an important role in the endoplasmic reticulum (ER) by facilitating the exchange of disulphide bonds and together with other ER stress proteins is induced in Amyotrophic Lateral Sclerosis (ALS). However, genetic polymorphisms in the P4HB gene, which encodes PDI, have not been thoroughly investigated in ALS cases. In this study, we determined whether single nucleotide polymorphisms (SNPs) in the P4HB gene were associated with Familial ALS (FALS) and Sporadic ALS (SALS). We report significant genotypic associations for two SNPs in P4HB with FALS, rs876016 (P=0.0198) and rs2070872 (P=0.0046), all values being FDR corrected. Significant allelic associations were also obtained for rs876016 with FALS (P=0.0155) and ALS (FALS and SALS) (P=0.0148). Four SNP haplotypes, which included two additional flanking SNPs, rs876017 and rs8324, were examined and rare haplotypes were found to be more common in ALS cases compared to controls. Seven haplotypes were found to be significantly associated with FALS and one haplotype was significantly associated with SALS. One rare haplotype, which was present in controls, was overrepresented in a group of SOD1 positive FALS cases. Reduced survival was observed in FALS cases possessing at least one copy of the minor allele of rs2070872 (P=0.0059) and rs8324 (P=0.0167) and in individuals lacking the homozygous AAAC/AAAC diplotype (P=0.011). The results suggest that P4HB is a modifier gene in ALS susceptibility and may represent a potential therapeutic target for ALS.
    Free Radical Biology and Medicine 01/2013; 58. DOI:10.1016/j.freeradbiomed.2013.01.001
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    • "Although SOD1 is essentially a cytosolic protein, a fraction of the normal as well as a mutated SOD1 pool was reported at the ER [141]. Interesting, PDI subcellular translocation to peripheral punctate structures accompanies protective effects of reticulon-4A (Nogo-A) on mutated SOD1-associated amyotrophic lateral sclerosis [142]. In contrast, PDI-mediated apoptosis Table 2 PDI posttranslational modifications beyond oxidation and reduction. "
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    ABSTRACT: Thiol proteins may potentially act as redox signaling adaptor proteins, adjusting reactive oxygen species intermediates to specific signals and redox signals to cell homeostasis. In this review, we discuss redox effects of protein disulfide isomerase (PDI), a thioredoxin superfamily oxidoreductase from the endoplasmic reticulum (ER). Abundantly expressed PDI displays ubiquity, interactions with redox and nonredox proteins, versatile effects, and several posttranslational modifications. The PDI family contains >20 members with at least some apparent complementary actions. PDI has oxidoreductase, isomerase, and chaperone effects, the last not directly dependent on its thiols. PDI is a converging hub for pathways of disulfide bond introduction into ER-processed proteins, via hydrogen peroxide-generating mechanisms involving the oxidase Ero1α, as well as hydrogen peroxide-consuming reactions involving peroxiredoxin IV and the novel peroxidases Gpx7/8. PDI is a candidate pathway for coupling ER stress to oxidant generation. Emerging information suggests a convergence between PDI and Nox family NADPH oxidases. PDI silencing prevents Nox responses to angiotensin II and inhibits Akt phosphorylation in vascular cells and parasite phagocytosis in macrophages. PDI overexpression spontaneously enhances Nox activation and expression. In neutrophils, PDI redox-dependently associates with p47phox and supports the respiratory burst. At the cell surface, PDI exerts transnitrosation, thiol reductase, and apparent isomerase activities toward targets including adhesion and matrix proteins and proteases. Such effects mediate redox-dependent adhesion, coagulation/thrombosis, immune functions, and virus internalization. The route of PDI externalization remains elusive. Such multiple redox effects of PDI may contribute to its conspicuous expression and functional role in disease, rendering PDI family members putative redox cell signaling adaptors.
    Free Radical Biology and Medicine 03/2012; 52(9):1954-69. DOI:10.1016/j.freeradbiomed.2012.02.037
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