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1.
Transl Psychiatry ; 3: e254, 2013 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-23632458

RESUMO

Claustrophobia, the well-known fear of being trapped in narrow/closed spaces, is often considered a conditioned response to traumatic experience. Surprisingly, we found that mutations affecting a single gene, encoding a stress-regulated neuronal protein, can cause claustrophobia. Gpm6a-deficient mice develop normally and lack obvious behavioral abnormalities. However, when mildly stressed by single-housing, these mice develop a striking claustrophobia-like phenotype, which is not inducible in wild-type controls, even by severe stress. The human GPM6A gene is located on chromosome 4q32-q34, a region linked to panic disorder. Sequence analysis of 115 claustrophobic and non-claustrophobic subjects identified nine variants in the noncoding region of the gene that are more frequent in affected individuals (P=0.028). One variant in the 3'untranslated region was linked to claustrophobia in two small pedigrees. This mutant mRNA is functional but cannot be silenced by neuronal miR124 derived itself from a stress-regulated transcript. We suggest that loosing dynamic regulation of neuronal GPM6A expression poses a genetic risk for claustrophobia.


Assuntos
Glicoproteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Transtornos Fóbicos/genética , Adulto , Tonsila do Cerebelo/química , Animais , Comportamento Animal , Eletrorretinografia , Feminino , Engenharia Genética/métodos , Heterozigoto , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Testes Psicológicos , Reflexo de Sobressalto/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estresse Psicológico/genética
2.
Mol Cell Neurosci ; 40(2): 156-66, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19026747

RESUMO

Myelin is organized in subdomains with distinct protein and lipid composition. How these domains are established and maintained is currently unknown. Cytoskeletal elements interacting with membrane components could generate and sustain such structural domains. Here, we demonstrate that the transmembrane myelin protein MAL interacts with the cytoskeleton protein septin 6. Septins represent a fourth filamentous system involved in membrane compartmentalization, vesicle transport and scaffold formation. We report that multiple septin complexes are associated with myelin, and that they display an overlapping but non-identical composition in the central and peripheral nervous system. The expression of distinct subsets of septins was upregulated during myelin formation in peripheral nerves and oligodendrocytes. In the PNS, septins were highly enriched in non-compact myelin compartments, particularly in the paranodal loops and the microvilli at the node of Ranvier. Importantly in myelin lacking Septin 6, the abundance of its closest homolog Sept11 was increased, suggesting a functional compensatory role. Our data demonstrate that the septin cytoskeleton is an integral component of the myelin sheath and interacts with distinct myelin constituents such as MAL. We suggest that septins are intriguing candidates for membrane compartmentalization in myelin internodes.


Assuntos
Citoesqueleto/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Bainha de Mielina/metabolismo , Neuroglia/fisiologia , Animais , Biomarcadores/metabolismo , Diferenciação Celular/fisiologia , Linhagem Celular , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Proteínas de Ligação ao GTP/genética , Humanos , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Proteínas da Mielina/genética , Proteínas da Mielina/metabolismo , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina , Neuroglia/citologia , Sistema Nervoso Periférico/metabolismo , Ligação Proteica , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteolipídeos/genética , Proteolipídeos/metabolismo , Ratos , Septinas , Técnicas do Sistema de Duplo-Híbrido
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