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: 6.34). 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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    • "PDI may protect against ER stress, inclusion formation and cell death associated with mutant SOD1 expression by modulating abnormal disulphide bond formation [27], [34]. In addition, the cellular distribution of PDI in mutant SOD1 transgenic mice modifies disease processes [35] and PDI is a constituent of TDP-43-positive or FUS-positive inclusions found in motor neurons of ALS patients [26], [36]. Cross-linking of TDP-43 via disulphide bonds alters its conformation and function [37], suggesting that PDI is a potential candidate for proteins that interact with TDP-43 and prevent TDP-43 misfolding. "
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    ABSTRACT: In amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, TAR DNA binding protein 43 (TDP-43) accumulates in the cytoplasm of affected neurons and glia, where it associates with stress granules (SGs) and forms large inclusions. SGs form in response to cellular stress, including endoplasmic reticulum (ER) stress, which is induced in both familial and sporadic forms of ALS. Here we demonstrate that pharmacological induction of ER stress causes TDP-43 to accumulate in the cytoplasm, where TDP-43 also associates with SGs. Furthermore, treatment with salubrinal, an inhibitor of dephosphorylation of eukaryotic initiation factor 2-α, a key modulator of ER stress, potentiates ER stress-mediated SG formation. Inclusions of C-terminal fragment TDP-43, reminiscent of disease-pathology, form in close association with ER and Golgi compartments, further indicating the involvement of ER dysfunction in TDP-43-associated disease. Consistent with this notion, over-expression of ALS-linked mutant TDP-43, and to a lesser extent wildtype TDP-43, triggers several ER stress pathways in neuroblastoma cells. Similarly, we found an interaction between the ER chaperone protein disulphide isomerase and TDP-43 in transfected cell lysates and in the spinal cords of mutant A315T TDP-43 transgenic mice. This study provides evidence for ER stress as a pathogenic pathway in TDP-43-mediated disease.
    PLoS ONE 11/2013; 8(11):e81170. DOI:10.1371/journal.pone.0081170 · 3.23 Impact Factor
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    • "ER stress causes the redistribution of PDIA1 and PDIA3 from the ER to the cytosol [178], consistent with the notion that PDI in locations other than the ER is neuroprotective. Furthermore, one study demonstrated that overexpression of reticulon-4A (NOGO A) triggered the redistribution of PDI from the ER into vesicular-type structures localized in an undefined cellular compartment, both in vitro and in vivo, which occurred in the absence of the UPR [179]. Deletion of NOGO A, B from ALS mouse models, involving transgenic overexpression of mutant SOD1G93A, led to earlier onset and increased disease progression, indicating that reticulons mediate PDI function and redistribution in neurodegeneration [179]. "
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    ABSTRACT: Neurodegenerative diseases involve the progressive loss of neurons, and a pathological hallmark is the presence of abnormal inclusions containing misfolded proteins. Although the precise molecular mechanisms triggering neurodegeneration remain unclear, endoplasmic reticulum (ER) stress, elevated oxidative and nitrosative stress, and protein misfolding are important features in pathogenesis. Protein disulphide isomerase (PDI) is the prototype of a family of molecular chaperones and foldases upregulated during ER stress that are increasingly implicated in neurodegenerative diseases. PDI catalyzes the rearrangement and formation of disulphide bonds, thus facilitating protein folding, and in neurodegeneration may act to ameliorate the burden of protein misfolding. However, an aberrant posttranslational modification of PDI, S-nitrosylation, inhibits its protective function in these conditions. S-nitrosylation is a redox-mediated modification that regulates protein function by covalent addition of nitric oxide- (NO-) containing groups to cysteine residues. Here, we discuss the evidence for abnormal S-nitrosylation of PDI (SNO-PDI) in neurodegeneration and how this may be linked to another aberrant modification of PDI, S-glutathionylation. Understanding the role of aberrant S-nitrosylation/S-glutathionylation of PDI in the pathogenesis of neurodegenerative diseases may provide insights into novel therapeutic interventions in the future.
    International Journal of Cell Biology 11/2013; 2013(1):797914. DOI:10.1155/2013/797914
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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 · 3.68 Impact Factor
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