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1.
Hum Mol Genet ; 27(12): 2154-2170, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29868845

RESUMO

Heterozygosity for the TOR1A-Δgag mutation causes semi-penetrant childhood-onset dystonia (OMIM #128100). More recently, homozygous TOR1A mutations were shown to cause severe neurological dysfunction in infants. However, there is little known about the recessive cases, including whether existing reports define the full spectrum of recessive TOR1A disease. Here we describe abnormal brain morphogenesis in ∼30% of Tor1a-/- mouse embryos while, in contrast, this is not found in Tor1aΔgag/Δgag mice. The abnormal Tor1a-/- brains contain excess neural tissue, as well as proliferative zone cytoarchitectural defects related to radial glial cell polarity and cytoskeletal organization. In cultured cells torsinA effects the linker of nucleoskeleton and cytoskeleton (LINC) complex that couples the nucleus and cytoskeleton. Here we identify that torsinA loss elevates LINC complex levels in the proliferative zone, and that genetic reduction of LINC complexes prevents abnormal brain morphogenesis in Tor1a-/- embryos. These data show that Tor1a affects radial glial cells via a LINC complex mediated mechanism. They also predict human TOR1A disease will include incompletely penetrant defects in embryonic brain morphogenesis in cases where mutations ablate TOR1A function.


Assuntos
Distonia/genética , Chaperonas Moleculares/genética , Morfogênese/genética , Neurogênese/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Modelos Animais de Doenças , Distonia/fisiopatologia , Heterozigoto , Homozigoto , Humanos , Camundongos , Camundongos Knockout , Neurônios , Matriz Nuclear/genética
2.
Neurobiol Dis ; 108: 128-139, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28823931

RESUMO

Striatal dysfunction is implicated in many movement disorders. However, the precise nature of defects often remains uncharacterized, which hinders therapy development. Here we examined striatal function in a mouse model of the incurable movement disorder, myoclonus dystonia, caused by SGCE mutations. Using RNAseq we found surprisingly normal gene expression, including normal levels of neuronal subclass markers to strongly suggest that striatal microcircuitry is spared by the disease insult. We then functionally characterized Sgce mutant medium spiny projection neurons (MSNs) and cholinergic interneurons (ChIs). This revealed normal intrinsic electrophysiological properties and normal responses to basic excitatory and inhibitory neurotransmission. Nevertheless, high-frequency stimulation in Sgce mutants failed to induce normal long-term depression (LTD) at corticostriatal glutamatergic synapses. We also found that pharmacological manipulation of MSNs by inhibiting adenosine 2A receptors (A2AR) restores LTD, again pointing to structurally intact striatal circuitry. The fact that Sgce loss specifically inhibits LTD implicates this neurophysiological defect in myoclonus dystonia, and emphasizes that neurophysiological changes can occur in the absence of broad striatal dysfunction. Further, the positive effect of A2AR antagonists indicates that this drug class be tested in DYT11/SGCE dystonia.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Corpo Estriado/efeitos dos fármacos , Distúrbios Distônicos/tratamento farmacológico , Plasticidade Neuronal/efeitos dos fármacos , Animais , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Distúrbios Distônicos/fisiopatologia , Feminino , Ácido Glutâmico/metabolismo , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Plasticidade Neuronal/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Técnicas de Patch-Clamp , RNA Mensageiro/metabolismo , Receptor A2A de Adenosina/metabolismo , Sarcoglicanas/genética , Sarcoglicanas/metabolismo , Técnicas de Cultura de Tecidos
3.
J Cell Sci ; 128(15): 2854-65, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26092934

RESUMO

TorsinA (also known as torsin-1A) is a membrane-embedded AAA+ ATPase that has an important role in the nuclear envelope lumen. However, most torsinA is localized in the peripheral endoplasmic reticulum (ER) lumen where it has a slow mobility that is incompatible with free equilibration between ER subdomains. We now find that nuclear-envelope-localized torsinA is present on the inner nuclear membrane (INM) and ask how torsinA reaches this subdomain. The ER system contains two transmembrane proteins, LAP1 and LULL1 (also known as TOR1AIP1 and TOR1AIP2, respectively), that reversibly co-assemble with and activate torsinA. Whereas LAP1 localizes on the INM, we show that LULL1 is in the peripheral ER and does not enter the INM. Paradoxically, interaction between torsinA and LULL1 in the ER targets torsinA to the INM. Native gel electrophoresis reveals torsinA oligomeric complexes that are destabilized by LULL1. Mutations in torsinA or LULL1 that inhibit ATPase activity reduce the access of torsinA to the INM. Furthermore, although LULL1 binds torsinA in the ER lumen, its effect on torsinA localization requires cytosolic-domain-mediated oligomerization. These data suggest that LULL1 oligomerizes to engage and transiently disassemble torsinA oligomers, and is thereby positioned to transduce cytoplasmic signals to the INM through torsinA.


Assuntos
Proteínas de Transporte/metabolismo , Retículo Endoplasmático/metabolismo , Proteínas de Membrana/metabolismo , Chaperonas Moleculares/metabolismo , Membrana Nuclear/metabolismo , Células 3T3 , Adenosina Trifosfatases/metabolismo , Animais , Células CHO , Proteínas de Transporte/genética , Linhagem Celular , Cricetulus , Proteínas de Membrana/genética , Camundongos , Complexos Multiproteicos/genética , Proteínas Nucleares/metabolismo , Ligação Proteica
4.
Dev Cell ; 38(3): 235-47, 2016 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-27453503

RESUMO

Torsins are developmentally essential AAA+ proteins, and mutation of human torsinA causes the neurological disease DYT1 dystonia. They localize in the ER membranes, but their cellular function remains unclear. We now show that dTorsin is required in Drosophila adipose tissue, where it suppresses triglyceride levels, promotes cell growth, and elevates membrane lipid content. We also see that human torsinA at the inner nuclear membrane is associated with membrane expansion and elevated cellular lipid content. Furthermore, the key lipid metabolizing enzyme, lipin, is mislocalized in dTorsin-KO cells, and dTorsin increases levels of the lipin substrate, phosphatidate, and reduces the product, diacylglycerol. Finally, genetic suppression of dLipin rescues dTorsin-KO defects, including adipose cell size, animal growth, and survival. These findings identify that torsins are essential regulators of cellular lipid metabolism and implicate disturbed lipid biology in childhood-onset DYT1 dystonia.


Assuntos
Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Metabolismo dos Lipídeos , Chaperonas Moleculares/metabolismo , Membrana Nuclear/metabolismo , Fosfatidato Fosfatase/metabolismo , Tecido Adiposo/metabolismo , Animais , Células Cultivadas , Diglicerídeos/metabolismo , Drosophila melanogaster/genética , Retículo Endoplasmático/metabolismo , Feminino , Humanos , Masculino , Lipídeos de Membrana/metabolismo , Chaperonas Moleculares/genética , Fosfolipídeos/metabolismo
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