RESUMO
Loss of fragile X messenger ribonucleoprotein (FMRP) causes fragile X syndrome (FXS), the most prevalent form of inherited intellectual disability. Here, we show that FMRP interacts with the voltage-dependent anion channel (VDAC) to regulate the formation and function of endoplasmic reticulum (ER)-mitochondria contact sites (ERMCSs), structures that are critical for mitochondrial calcium (mito-Ca2+) homeostasis. FMRP-deficient cells feature excessive ERMCS formation and ER-to-mitochondria Ca2+ transfer. Genetic and pharmacological inhibition of VDAC or other ERMCS components restored synaptic structure, function, and plasticity and rescued locomotion and cognitive deficits of the Drosophila dFmr1 mutant. Expressing FMRP C-terminal domain (FMRP-C), which confers FMRP-VDAC interaction, rescued the ERMCS formation and mito-Ca2+ homeostasis defects in FXS patient iPSC-derived neurons and locomotion and cognitive deficits in Fmr1 knockout mice. These results identify altered ERMCS formation and mito-Ca2+ homeostasis as contributors to FXS and offer potential therapeutic targets.
Assuntos
Proteínas de Drosophila , Síndrome do Cromossomo X Frágil , Animais , Camundongos , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Cálcio/metabolismo , Proteína do X Frágil da Deficiência Intelectual/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Drosophila/metabolismo , Camundongos Knockout , Homeostase , Mitocôndrias/metabolismo , Retículo Endoplasmático/metabolismo , Canais de Ânion Dependentes de Voltagem/metabolismo , Proteínas de Drosophila/metabolismoRESUMO
Perimesencephalic subarachnoid hemorrhage (PM-SAH) refers to intracranial hemorrhage located in the perimesencephalic cistern. The etiology remains mainly unclear, although venous leakage or rupture has been postulated. We report an interesting case of a 57-year-old healthy man who presented initially with PM-SAH with worsening of subcortical lesions on follow-up neuroimaging. Histopathological examination demonstrated cerebral amyloid angiopathy with perivascular inflammation.
