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1.
Cell Rep ; 43(6): 114256, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38795343

RESUMO

The decline of motor ability is a hallmark feature of aging and is accompanied by degeneration of motor synaptic terminals. Consistent with this, Drosophila motor synapses undergo characteristic age-dependent structural fragmentation co-incident with diminishing motor ability. Here, we show that motor synapse levels of Trio, an evolutionarily conserved guanine nucleotide exchange factor (GEF), decline with age. We demonstrate that increasing Trio expression in adult Drosophila can abrogate age-dependent synaptic structural fragmentation, postpone the decline of motor ability, and maintain the capacity of motor synapses to sustain high-intensity neurotransmitter release. This preservative activity is conserved in transgenic human Trio, requires Trio Rac GEF function, and can also ameliorate synapse degeneration induced by depletion of miniature neurotransmission. Our results support a paradigm where the structural dissolution of motor synapses precedes and promotes motor behavioral diminishment and where intervening in this process can postpone the decline of motor function during aging.


Assuntos
Envelhecimento , Sinapses , Animais , Envelhecimento/fisiologia , Sinapses/metabolismo , Humanos , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Fatores de Troca do Nucleotídeo Guanina/genética , Drosophila melanogaster/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Neurônios Motores/metabolismo , Atividade Motora , Transmissão Sináptica , Proteínas Serina-Treonina Quinases
2.
J Clin Invest ; 133(10)2023 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-36976648

RESUMO

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.


Assuntos
Ceramidas , Esfingolipídeos , Humanos , Ceramidas/metabolismo , Homeostase , Mutação , Esfingolipídeos/genética , Esfingolipídeos/metabolismo
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