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      Autoimmune septin-5 cerebellar ataxia

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          Abstract

          Objective

          To report a form of autoimmune cerebellar ataxia in which antibodies target septin-5, a guanosine triphosphate (GTP)-binding neural protein involved in neurotransmitter exocytosis.

          Methods

          Archived sera and CSF specimens with unclassified synaptic antibodies were re-evaluated by tissue-based indirect immunofluorescence assay. Autoantigens were identified by Western blot and mass spectrometry. Recombinant protein assays (Western blot, cell based, and protein screening array) confirmed antigen specificity.

          Results

          Serum and CSF from 6 patients produced identical synaptic immunoglobulin G (IgG) staining patterns of synaptic regions (neuropil) of the mouse cerebrum and cerebellum. The molecular layer of the cerebellum and the thalamus demonstrated stronger immunoreactivity than the midbrain, hippocampus, cortex, and basal ganglia. The antigen revealed by mass spectrometry analysis of immunoprecipitated cerebellar proteins and confirmed by recombinant protein assays was septin-5. All 4 patients with records available had subacute onset of cerebellar ataxia with prominent eye movement symptoms (oscillopsia or vertigo). None had cancer detected. Improvements occurred after immunotherapies (2) or spontaneously (1). One patient died.

          Conclusion

          Septin-5 IgG represents a biomarker for a potentially fatal but treatable autoimmune ataxia.

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          Most cited references9

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          The Mammalian Septin Interactome

          Katharina Neubauer, Barbara Zieger (2017)
          Septins are GTP-binding and membrane-interacting proteins with a highly conserved domain structure involved in various cellular processes, including cytoskeleton organization, cytokinesis, and membrane dynamics. To date, 13 different septin genes have been identified in mammals (SEPT1 to SEPT12 and SEPT14), which can be classified into four distinct subgroups based on the sequence homology of their domain structure (SEPT2, SEPT3, SEPT6, and SEPT7 subgroup). The family members of these subgroups have a strong affinity for other septins and form apolar tri-, hexa-, or octameric complexes consisting of multiple septin polypeptides. The first characterized core complex is the hetero-trimer SEPT2-6-7. Within these complexes single septins can be exchanged in a subgroup-specific manner. Hexamers contain SEPT2 and SEPT6 subgroup members and SEPT7 in two copies each whereas the octamers additionally comprise two SEPT9 subgroup septins. The various isoforms seem to determine the function and regulation of the septin complex. Septins self-assemble into higher-order structures, including filaments and rings in orders, which are typical for different cell types. Misregulation of septins leads to human diseases such as neurodegenerative and bleeding disorders. In non-dividing cells such as neuronal tissue and platelets septins have been associated with exocytosis. However, many mechanistic details and roles attributed to septins are poorly understood. We describe here some important mammalian septin interactions with a special focus on the clinically relevant septin interactions.
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            Septins regulate developmental switching from microdomain to nanodomain coupling of Ca(2+) influx to neurotransmitter release at a central synapse.

            Yi-Mei Yang, Michael J Fedchyshyn, Giovanbattista Grande … (2010)
            Neurotransmitter release depends critically on close spatial coupling of Ca(2+) entry to synaptic vesicles at the nerve terminal; however, the molecular substrates determining their physical proximity are unknown. Using the calyx of Held synapse, where "microdomain" coupling predominates at immature stages and developmentally switches to "nanodomain" coupling, we demonstrate that deletion of the filamentous protein Septin 5 imparts immature synapses with striking morphological and functional features reminiscent of mature synapses. This includes synaptic vesicles tightly localized to active zones, resistance to the slow Ca(2+) buffer EGTA and a reduced number of Ca(2+) channels required to trigger single fusion events. Disrupting Septin 5 organization acutely transforms microdomain to nanodomain coupling and potentiates quantal output in immature wild-type terminals. These observations suggest that Septin 5 is a core molecular substrate that differentiates distinct release modalities at the central synapse.
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              Septin dynamics are essential for exocytosis.

              Elizabeth Marcus, Julian P Whitelegge, Venera Khuzakhmetova … (2015)
              Septins are a family of 14 cytoskeletal proteins that dynamically form hetero-oligomers and organize membrane microdomains for protein complexes. The previously reported interactions with SNARE proteins suggested the involvement of septins in exocytosis. However, the contradictory results of up- or down-regulation of septin-5 in various cells and mouse models or septin-4 in mice suggested either an inhibitory or a stimulatory role for these septins in exocytosis. The involvement of the ubiquitously expressed septin-2 or general septin polymerization in exocytosis has not been explored to date. Here, by nano-LC with tandem MS and immunoblot analyses of the septin-2 interactome in mouse brain, we identified not only SNARE proteins but also Munc-18-1 (stabilizes assembled SNARE complexes), N-ethylmaleimide-sensitive factor (NSF) (disassembles SNARE complexes after each membrane fusion event), and the chaperones Hsc70 and synucleins (maintain functional conformation of SNARE proteins after complex disassembly). Importantly, α-soluble NSF attachment protein (SNAP), the adaptor protein that mediates NSF binding to the SNARE complex, did not interact with septin-2, indicating that septins undergo reorganization during each exocytosis cycle. Partial depletion of septin-2 by siRNA or impairment of septin dynamics by forchlorfenuron inhibited constitutive and stimulated exocytosis of secreted and transmembrane proteins in various cell types. Forchlorfenuron impaired the interaction between SNAP-25 and its chaperone Hsc70, decreasing SNAP-25 levels in cultured neuroendocrine cells, and inhibited both spontaneous and stimulated acetylcholine secretion in mouse motor neurons. The results demonstrate a stimulatory role of septin-2 and the dynamic reorganization of septin oligomers in exocytosis.
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                Author and article information

                Contributors
                Josephe A. Honorat:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. a patent application is pending for Septin-5-IgG as biomarker of autoimmune neurological disease.

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                A. Sebastian Lopez-Chiriboga:
                Comment :

                Scientific Advisory Boards:

                1. NONE

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                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Thomas J. Kryzer:
                Comment :

                Scientific Advisory Boards:

                1. NONE

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                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. I have financial interest in the following intellectual property: ?Marker for Neuromyelitis Optica.? A patent has been issued for this technology, and it has been licensed to commercial entities. I have received cumulative royalties of greater than the federal threshold for significant financial interest from the licensing of these technologies, but receive no royalties from the sale of these tests by Mayo Medical

                Stock/Stock Options, Research Sponsor:

                1. NONE

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                1. NONE

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                1. NONE

                James P. Fryer:
                Comment :

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                1. NONE

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                1. NONE

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                1. NONE

                Editorial Boards:

                1. NONE

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                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

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                1. NONE

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                1. NONE

                Legal Proceedings:

                1. NONE

                Michelle Devine:
                Comment :

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                1. NONE

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                1. NONE

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                1. NONE

                Editorial Boards:

                1. NONE

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                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

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                1. NONE

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                1. NONE

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                1. NONE

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                1. NONE

                Angela Flores:
                Comment :

                Scientific Advisory Boards:

                1. NONE

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                1. NONE

                Funding for travel or speaker honoraria:

                1. Biogen, Multiple sclerosis Association of America

                Editorial Boards:

                1. NONE

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                1. NONE

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                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. Advisory board

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                1. Biogen

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                1. NONE

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                1. NONE

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                1. NONE

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                1. NONE

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                1. NONE

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                1. NONE

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                1. NONE

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                Vanda A. Lennon:
                Comment :

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                1. NONE

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                1. Vanda Lennon receives royalties from RSR/Kronus for sale of aquaporin-4 autoantibody testing kits and for commercial aquaporin-4 autoantibody testing performed outside Mayo Clinic.

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

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                1. NONE

                Speakers' Bureaus:

                1. NONE

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                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. MN Partnership for Biotechnology and Medical Genomics, grant # ML2017, Chapter 89, Art, section #4 (e) Sub-award # P007067701

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License fee payments, Technology or Inventions:

                1. 1) RSR/Kronus for sale of aquaporin-4 autoantibody testing kits. 2) Non-Mayo sites performing

                Royalty Payments, Technology or Inventions:

                1. Dr. Lennon has a potential financial interest in the technologies listed below:

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                1. NONE

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                1. NONE

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                Sean J. Pittock:
                Comment :

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                1. NONE

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                1. Dr. Pittock and Mayo Clinic have a financial interest in patents (#12/678,350 filed 2010 and #12/573,942 filed 2008) that relate to functional AQP4/NMO-IgG assays and NMO-IgG as a cancer marker. Dr Pittock has a patent pending for Septin-5 and MAP1B autoantibodies as biomarkers of neurological autoimmunity.

                Publishing Royalties:

                1. NONE

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                1. NONE

                Consultancies:

                1. Dr. Pittock has provided consultation to Alexion Pharmaceuticals and Medimmune but has received no personal fees or personal compensation for these consulting activities. All compensation for consulting activities is paid directly to Mayo Clinic.

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                1. NONE

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                1. Dr Pittock has received research funding from Grifols, Medimmune and Alexion.

                Research Support, Government Entities:

                1. RO1 NS065829-01

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                1. NONE

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                1. NONE

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                1. NONE

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                Andrew McKeon:
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                1. NONE

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                1. Patent applications pending: Septin 5 and MAP1B as markers of neurological autoimmunity and paraneoplastic disorders

                Publishing Royalties:

                1. NONE

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                1. NONE

                Consultancies:

                1. Grifols Medimmune Euroimmun No personal compensation received for these activities

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                1. NONE

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                1. NONE

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                1. NONE

                Research Support, Commercial Entities:

                1. Medimmune, Inc Euroimmun

                Research Support, Government Entities:

                1. NONE

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                1. NONE

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                1. NONE

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                1. NONE

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                1. NONE

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                Journal
                Journal ID (nlm-ta): Neurol Neuroimmunol Neuroinflamm
                Journal ID (iso-abbrev): Neurol Neuroimmunol Neuroinflamm
                Journal ID (hwp): nnn
                Journal ID (publisher-id): NEURIMMINFL
                Title: Neurology® Neuroimmunology & Neuroinflammation
                Publisher: Lippincott Williams & Wilkins (Hagerstown, MD )
                ISSN (Electronic): 2332-7812
                Publication date (Electronic): 09 July 2018
                Publication date Collection: September 2018
                Publication date PMC-release: 09 July 2018
                Volume: 5
                Issue: 5
                Electronic Location Identifier: e474
                Affiliations
                From the Department of Laboratory Medicine and Pathology (J.A.H., T.J.K., J.P.F., V.A.L., S.J.P., A.M.), the Department of Neurology (A.S.L.-C., V.A.L., S.J.P., A.M.), and the Department of Immunology (V.A.L.), College of Medicine, Mayo Clinic, Rochester, MN; and Department of Neurology (M.D., A.F.), University of Texas, Southwestern, Dallas.
                Author notes
                Correspondence Dr. McKeon mckeon.andrew@ 123456mayo.edu

                Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NN.

                The Article Processing Charge was funded by the authors.

                Article
                Publisher ID: NEURIMMINFL2018016303
                DOI: 10.1212/NXI.0000000000000474
                PMC ID: 6039209
                PubMed ID: 29998156
                SO-VID: d198f0b4-e87d-49e6-bd04-14b919414a34
                Copyright © Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

                History
                Date received : 01 March 2018
                Date accepted : 21 May 2018
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