Antiamphiphysin Antibodies Are Associated With Various Paraneoplastic Neurological Syndromes and Tumors

Antoine, J. C.; Absi, Léna; Honnorat, Jérôme; Boulesteix, Jean-Marc; Brouker, Thomas de; Vial, Christophe; Butler, Margareth; Camilli, Pietro De; Michel, D

doi:10.1001/archneur.56.2.172

Cited by 144 publications

(74 citation statements)

References 17 publications

(17 reference statements)

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“…The proteins that do appear to be associated with O-GlcNAcase include heat shock proteins (HSP110 and HSC70) and intracellular signal transducers (amphiphysin, DRP-2, and calcineurin). It is interesting to note that deregulation of amphiphysin, DRP-2, and calcineurin have all been associated with neurological diseases (33)(34)(35). Also, several O-GlcNAc-modified proteins, including neurofilaments, tau, and the ␤-amyloid protein, are implicated in neurological disorders (36,37).…”

Section: Discussionmentioning

confidence: 99%

Dynamic O-Glycosylation of Nuclear and Cytosolic Proteins

Wells¹,

Gao²,

Mahoney³

et al. 2002

Journal of Biological Chemistry

219

131

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␤-O-linked N-acetylglucosamine (O-GlcNAc) is an abundant and dynamic post-translational modification implicated in protein regulation that appears to be functionally more similar to phosphorylation than to classical glycosylation. There are nucleocytoplasmic enzymes for the attachment and removal of O-GlcNAc. Here, we further characterize the recently cloned ␤-N-acetylglucosaminidase, O-GlcNAcase. Both recombinant and purified endogenous O-GlcNAcase rapidly release free GlcNAc from O-GlcNAc-modified peptide substrates. The recombinant enzyme functions as a monomer and has kinetic parameters (K m ‫؍‬ 1.1 mM for paranitrophenyl-GlcNAc, k cat ‫؍‬ 1 s ؊1 ) that are similar to those of lysosomal hexosaminidases. The endogenous O-GlcNAcase appears to be in a complex with other proteins and is predominantly localized to the cytosol. Overexpression of the enzyme in living cells results in decreased O-GlcNAc modification of nucleocytoplasmic proteins. Finally, we show that the enzyme is a substrate for caspase-3 but, suprisingly, the cleavage has no effect on in vitro O-GlcNAcase activity. These studies support the identification of this protein as an O-GlcNAcase and identify important interactions and modifications that may regulate the enzyme and O-GlcNAc cycling.Multiple nucleocytoplasmic proteins, including transcription factors, cytoskeletal proteins, oncogenes, and kinases, are posttranslationally modified with ␤-N-acetylglucosamine (O-GlcNAc) 1 (1-3). In each case studied, the glycan has a turnover rate that is much faster than that of the protein to which it is attached (4, 5). The O-GlcNAc modification of certain proteins is modulated by various extracellular stimuli and growth conditions (6, 7). Thus, based on its dynamic and inducible nature, O-GlcNAc is most likely a regulatory modification, more similar to phosphorylation than to classical glycosylation (8). In further support of this hypothesis, there are nucleocytoplasmic enzymes for the attachment (O-GlcNAc transferase, OGT) and for the removal (O-GlcNAcase) of O-GlcNAc, analogous to the kinases and phosphatases for phosphate.The protein uridine diphospho-N-acetylglucosamine: polypeptide ␤-N-acetylglucosaminyltransferase (OGT) has been cloned and characterized in our laboratory and others (10, 11). OGT is highly conserved from Caenorhabditis elegans to humans and is essential for mouse embryonic stem cell viability (12). OGT contains multiple tetratricopeptide repeats that appear to mediate the enzyme's trimerization, substrate recognition, and protein-protein interactions (13,14). Furthermore, the enzyme is modified by tyrosine phosphorylation, as well as O-GlcNAc (10). A variety of splice variants of this enzyme appear in the National Center for Biotechnology Information data base, but they have not been examined. The enzyme is also exquisitely responsive to the concentration of UDP-GlcNAc, the donor sugar nucleotide (13). This multitude of protein-binding domains, post-translational modifications, splice variants, and substrate sensitivity could allow ...

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Section: Discussionmentioning

confidence: 99%

Dynamic O-Glycosylation of Nuclear and Cytosolic Proteins

Wells¹,

Gao²,

Mahoney³

et al. 2002

Journal of Biological Chemistry

219

131

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“…There have been only 2 reported cases with LEMS that preceded subacute CA 2,3 . In this respect, our patient is a rare case.…”

Section: Discussionmentioning

confidence: 99%

Transient subacute cerebellar ataxia in a patient with Lambert-Eaton myasthenic syndrome after intracranial aneurysm surgery

Nakamura

Yabe

Sato

et al. 2008

Clinical Neurology and Neurosurgery

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*These authors contributed equally to this work. AbstractSeveral reports have presented patients with subacute cerebellar ataxia (subacute CA) and Lambert-Eaton myasthenic syndrome (LEMS). Some clinical features of those patients have been described in the previous reports, such as priority of subacute CA to LEMS or a concurrent occurrence of both diseases, a high incidence of malignancy, less efficacy of the treatment for subacute CA compared with that for LEMS. Cerebellar ataxia in some patients with LEMS has been demonstrated to be caused by serum antibodies to P/Q-type voltage-gated calcium channels (VGCCs). Here, we report a 63-year-old woman with subacute CA and LEMS. Cerebellar ataxia appeared 15 months after the incidence of LEMS, and the onset of cerebellar ataxia was thought to be due to serum anti-P/Q-type VGCCs antibodies. The clinical course of this patient was atypical in that 1) LEMS preceded subacute CA which developed after intracranial aneurysm surgery, 2) no malignancy was detected when both diseases coexisted, 3) symptoms of LEMS did not progress with the onset of cerebellar ataxia, and 4) cerebellar ataxia showed a definite improvement in symptoms and by 123 I-IMP SPECT imaging after steroid administration. In addition, it is remarkable that LEMS became aggravated in electrophysiological examinations in contrast to subacute CA. We suggest that these atypical features of subacute CA and the changes in LEMS may be associated with a balance between the amount of serum anti-P/Q-type VGCCs antibodies and the susceptibility of the cerebellum and presynaptic nerve terminals to the antibodies. More cases are needed to investigate the mechanisms involved. The subacute CA and LEMS in this patient have remained comparatively silent after the withdrawal of steroid, and we are continuing to observe her condition.

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“…One patient series evaluated the frequency of anti-amphiphysin antibodies in paraneoplastic disorders at 5/2,800 [6]. A more recent and larger series estimated this frequency to be 71 of 120,000 sera submitted for paraneoplastic auto-antibody evaluation (0.06%), a figure about 7 times lower than for ANNA-I and CRMP-5/CV2 antibodies [10].…”

Section: Discussionmentioning

confidence: 99%

“…An auto-immune response to this protein was first reported in stiff man syndrome (SMS) associ ated with breast cancer [1,2,3], and is observed rarely in other paraneoplastic neurological disorders [4,5,6,7,8,9,10]. Anti-amphiphysin antibodies (AAAb) frequently coexist with other paraneoplastic antibodies, especially anti-collapsin response mediator protein (CRMP)-5/CV2 and anti-Hu (anti-neuronal nuclear antibody type I or ANNA-I) antibodies [10, 11].…”

Section: Introductionmentioning

confidence: 99%

Paraneoplastic Rhombencephalitis and Brachial Plexopathy in Two Cases of Amphiphysin Auto-Immunity

et al. 2006

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Amphiphysin, a synaptic vesicle protein, is an auto-immune target in rare cases of paraneoplastic neurological disorders. We report two additional cases with distinct neurological syndromes and paraneoplastic anti-amphiphysin antibodies. The first patient, a 59-year-old man, presented with cerebellar and cranial nerve dysfunction and small cell lung carcinoma. The second, a 77-year- old woman, presented with left brachial plexopathy followed by sensorimotor neuropathy and breast carcinoma.

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Antiamphiphysin Antibodies Are Associated With Various Paraneoplastic Neurological Syndromes and Tumors

Cited by 144 publications

References 17 publications

Dynamic O-Glycosylation of Nuclear and Cytosolic Proteins

Dynamic O-Glycosylation of Nuclear and Cytosolic Proteins

Transient subacute cerebellar ataxia in a patient with Lambert-Eaton myasthenic syndrome after intracranial aneurysm surgery

Paraneoplastic Rhombencephalitis and Brachial Plexopathy in Two Cases of Amphiphysin Auto-Immunity

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