RESUMO
The protein α-synuclein has a central role in Parkinson disease, but the mechanism by which it contributes to neural degeneration remains unknown. We now show that the expression of α-synuclein in mammalian cells, including neurons in vitro and in vivo, causes the fragmentation of mitochondria. The effect is specific for synuclein, with more fragmentation by α- than ß- or γ-isoforms, and it is not accompanied by changes in the morphology of other organelles or in mitochondrial membrane potential. However, mitochondrial fragmentation is eventually followed by a decline in respiration and neuronal death. The fragmentation does not require the mitochondrial fission protein Drp1 and involves a direct interaction of synuclein with mitochondrial membranes. In vitro, synuclein fragments artificial membranes containing the mitochondrial lipid cardiolipin, and this effect is specific for the small oligomeric forms of synuclein. α-Synuclein thus exerts a primary and direct effect on the morphology of an organelle long implicated in the pathogenesis of Parkinson disease.
Assuntos
Mitocôndrias/metabolismo , Neurônios/metabolismo , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Animais , Células COS , Morte Celular/genética , Chlorocebus aethiops , Células HeLa , Humanos , Potencial da Membrana Mitocondrial/genética , Membranas Artificiais , Camundongos , Mitocôndrias/genética , Mitocôndrias/patologia , Neurônios/patologia , Consumo de Oxigênio/genética , Doença de Parkinson/genética , Doença de Parkinson/patologia , alfa-Sinucleína/química , alfa-Sinucleína/genéticaRESUMO
The PSD-95 family of proteins, known as MAGUKs, have long been recognized to be central building blocks of the PSD. They are categorized as scaffolding proteins, which link surface-expressed receptors to the intracellular signaling molecules. Although the four members of the PSD-95 family (PSD-95, PSD-93, SAP102, and SAP97) have many shared roles in regulating synaptic function, recent studies have begun to delineate specific binding partners and roles in plasticity. In the current review, we will highlight the conserved and unique roles of these proteins.