Selective loss of Purkinje cells in a patient with anti-gliadin-antibody-positive autoimmune cerebellar ataxia

Abstract Background To report a novel autoantibody against Purkinje cell in a patient with autoimmune cerebellar ataxia (ACA) associated to Sjogren’s syndrome (SS).Methods The Patients on one centre with cerebellar ataxia of unknown cause, who were tested positive with tissue-based indirect immunofluorescence assay (TBA) on rat cerebellum sections and negative for comprehensive anti-neural autoantibodies panel, were investigated for novel autoantibody identification. Among them, one patient with comorbid ACA and SS was qualified for further exploration. His-immunoprecipitation (HIP) combined with mass spectrometric (MS) analysis was used to identify the target antigen, which was confirmed by recombinant cell based assay (CBA) and antibody neutralization experiments. Results TBA of the patient’s serum and cerebrospinal fluid (CSF) for autoantibody testing revealed binding of IgG antibody, mainly IgG1, to Purkinje cell and granular layer of rat cerebellum. Rab6A was identified as the autoantigen by MS and Western blot, subsequently verified by CBA with HEK293 cells expressing human Rab6A/Rab6B. Furthermore, recombinant human Rab6A/Rab6B protein to neutralize the autoantibodies’ tissue reaction was performed by a parallel confirmed approach.Conclusion Autoantibody against Rab6A/Rab6B may be a novel biomarker in diagnosis of ACA, especially in patients with comorbid ACA and SS. The role of the antibody in mechanism of ACA warrants further study.

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Human alpha-synuclein overexpressing MBP29 mice mimic functional and structural hallmarks of the cerebellar subtype of multiple system atrophy

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01166-x ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Lisa Mészáros ◽

Markus J. Riemenschneider ◽

Heiko Gassner ◽

Franz Marxreiter ◽

Stephan von Hörsten ◽

...

Keyword(s):

Mouse Model ◽

Multiple System Atrophy ◽

Cerebellar Ataxia ◽

Purkinje Cells ◽

Alpha Synuclein ◽

Significant Loss ◽

Disease Stage ◽

Cytoplasmic Inclusions ◽

Unsteady Gait ◽

Advanced Disease Stage

AbstractMultiple system atrophy (MSA) is a rare, but fatal atypical parkinsonian disorder. The prototypical pathological hallmark are oligodendroglial cytoplasmic inclusions (GCIs) containing alpha-synuclein (α-syn). Currently, two MSA phenotypes are classified: the parkinsonian (MSA-P) and the cerebellar subtype (MSA-C), clinically characterized by predominant parkinsonism or cerebellar ataxia, respectively. Previous studies have shown that the transgenic MSA mouse model overexpressing human α-syn controlled by the oligodendroglial myelin basic protein (MBP) promoter (MBP29-hα-syn mice) mirrors crucial characteristics of the MSA-P subtype. However, it remains elusive, whether this model recapitulates important features of the MSA-C-related phenotype. First, we examined MSA-C-associated cerebellar pathology using human post-mortem tissue of MSA-C patients and controls. We observed the prototypical GCI pathology and a preserved number of oligodendrocytes in the cerebellar white matter (cbw) accompanied by severe myelin deficit, microgliosis, and a profound loss of Purkinje cells. Secondly, we phenotypically characterized MBP29-hα-syn mice using a dual approach: structural analysis of the hindbrain and functional assessment of gait. Matching the neuropathological features of MSA-C, GCI pathology within the cbw of MBP29-hα-syn mice was accompanied by a severe myelin deficit despite an increased number of oligodendrocytes and a high number of myeloid cells even at an early disease stage. Intriguingly, MBP29-hα-syn mice developed a significant loss of Purkinje cells at a more advanced disease stage. Catwalk XT gait analysis revealed decreased walking speed, increased stride length and width between hind paws. In addition, less dual diagonal support was observed toward more dual lateral and three paw support. Taken together, this wide-based and unsteady gait reflects cerebellar ataxia presumably linked to the cerebellar pathology in MBP29-hα-syn mice. In conclusion, the present study strongly supports the notion that the MBP29-hα-syn mouse model mimics important characteristics of the MSA-C subtype providing a powerful preclinical tool for evaluating future interventional strategies.

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Diagnostic Criteria for Primary Autoimmune Cerebellar Ataxia—Guidelines from an International Task Force on Immune-Mediated Cerebellar Ataxias

The Cerebellum ◽

10.1007/s12311-020-01132-8 ◽

2020 ◽

Vol 19 (4) ◽

pp. 605-610 ◽

Cited By ~ 4

Author(s):

Marios Hadjivassiliou ◽

Francesc Graus ◽

Jerome Honnorat ◽

Sven Jarius ◽

Maarten Titulaer ◽

...

Keyword(s):

Diagnostic Criteria ◽

Cerebellar Ataxia ◽

Task Force ◽

Immune Mediated ◽

Autoimmune Cerebellar Ataxia ◽

Cerebellar Ataxias

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Selective loss of the GABAAα1 subunit from Purkinje cells is sufficient to induce a tremor phenotype

Journal of Neurophysiology ◽

10.1152/jn.00100.2020 ◽

2020 ◽

Vol 124 (4) ◽

pp. 1183-1197

Author(s):

Angela Nietz ◽

Chris Krook-Magnuson ◽

Haruna Gutierrez ◽

Julia Klein ◽

Clarke Sauve ◽

...

Keyword(s):

Essential Tremor ◽

Purkinje Cells ◽

Selective Loss

Animals with a global knockout of the GABAAα1 subunit show a tremor phenotype reminiscent of essential tremor. Here we show that selective knockout of GABAAα1 from Purkinje cells is sufficient to produce a tremor phenotype, although this tremor is less severe than seen in animals with a global knockout. These findings illustrate that the cerebellum can play a key role in the genesis of the observed tremor phenotype.

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Clinical characteristics of patients with cerebellar ataxia associated with anti-GAD antibodies

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20170011 ◽

2017 ◽

Vol 75 (3) ◽

pp. 142-146 ◽

Cited By ~ 4

Author(s):

Tiago Silva Aguiar ◽

Andrea Fragoso ◽

Carolina Rouanet de Albuquerque ◽

Patrícia de Fátima Teixeira ◽

Marcus Vinícius Leitão de Souza ◽

...

Keyword(s):

Cerebellar Ataxia ◽

Pancreatic Beta Cells ◽

Clinical Characteristics ◽

Immunoglobulin Therapy ◽

Acid Decarboxylase ◽

Partial Recovery ◽

Gamma Aminobutyric Acid ◽

Intravenous Immunoglobulin Therapy ◽

Autoimmune Cerebellar Ataxia ◽

Insidious Onset

ABSTRACT The enzyme glutamic acid decarboxylase (GAD), present in GABAergic neurons and in pancreatic beta cells, catalyzes the conversion of gamma-aminobutyric acid (GABA). The cerebellum is highly susceptible to immune-mediated mechanisms, with the potentially treatable autoimmune cerebellar ataxia associated with the GAD antibody (CA-GAD-ab) being a rare, albeit increasingly detected condition. Few cases of CA-GAD-ab have been described. Methods This retrospective and descriptive study evaluated the clinical characteristics and outcomes of patients with CA-GAD-ab. Result Three patients with cerebellar ataxia, high GAD-ab titers and autoimmune endocrine disease were identified. Patients 1 and 2 had classic stiff person syndrome and insidious-onset cerebellar ataxia, while Patient 3 had pure cerebellar ataxia with subacute onset. Patients received intravenous immunoglobulin therapy with no response in Patients 1 and 3 and partial recovery in Patient 2. Conclusion CA-GAD-ab is rare and its clinical presentation may hamper diagnosis. Clinicians should be able to recognize this potentially treatable autoimmune cerebellar ataxia.

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The Cerebellar Serotoninergic System and its Possible Involvement in Cerebellar Ataxia

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100048575 ◽

1993 ◽

Vol 20 (S3) ◽

pp. S78-S82 ◽

Cited By ~ 24

Author(s):

P. Trouillas

Keyword(s):

Cerebellar Ataxia ◽

Purkinje Cells ◽

Molecular Layer ◽

Cortical Atrophy ◽

Target Cells ◽

Serotoninergic System ◽

Synaptic Connections ◽

Cerebellar Syndrome ◽

Cerebellar Cortical Atrophy ◽

The Brain

ABSTRACT:A review concerning the characteristics of the cerebellar serotoninergic system is presented. In rat, cat and oppossum, the perikarya of origin are located in the brain stem raphe nuclei and in other brainstem structures. The projections to the cerebellar layers and deep nuclei include synaptic connections, but also non synaptic terminals, espedaily in a diffuse cortical plexus. Serotoninergic receptors have been described: 5-HT1B in the molecular layer and 5-HT2 in the inferior olive. Serotonin exerts neurophysiological effects on several target cells, directly or indirectly, presynaptically or postsynaptically. A modulatory effect on Purkinje cells is well documented. In thiamine deprived animals, a specific serotoninergic cerebellar syndrome includes a selective degeneration of the serotoninergic cerebellar system, an increase of the 5-HIAA cerebellar values and an exaggerated serotoninergic turnover. In human here-doataxias (Friedreich’s ataxia and cerebellar cortical atrophy), serotoninergic disturbances have been observed in the CSF, including low 5-HIAA values and an increased serotoninergic turnover. Therapeutic results have been obtained with L-5-HTP, a precursor of serotonin, in several conditions presenting cerebellar ataxia. L-5-HTP resistance of olivo-pontocerebellar atrophies may be explained by the destruction of serotonin-sensitive target cells, especially Purkinje cells.

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