RESUMO
Alpha-synuclein (αS) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying αS toxicity. Increasing evidence suggests that defects in membrane transport play an important role in neuronal dysfunction. Here we demonstrate that the GTPase Rab8a interacts with αS in rodent brain. NMR spectroscopy reveals that the C-terminus of αS binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/αS interaction, Rab8a enhanced αS aggregation and reduced αS-induced cellular toxicity. In addition, Rab8 - the Drosophila ortholog of Rab8a - ameliorated αS-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the αS-Rab8a interaction, phosphorylation of αS at S129 enhanced binding to Rab8a, increased formation of insoluble αS aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and αS cytotoxicity, and underscores the therapeutic potential of targeting this interaction.
Assuntos
Proteínas de Drosophila/metabolismo , GTP Fosfo-Hidrolases/metabolismo , alfa-Sinucleína/química , alfa-Sinucleína/metabolismo , Proteínas rab de Ligação ao GTP/química , Proteínas rab de Ligação ao GTP/metabolismo , Animais , Animais Geneticamente Modificados , Encéfalo/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Proteínas de Drosophila/genética , Drosophila melanogaster , Escherichia coli , GTP Fosfo-Hidrolases/genética , Humanos , Camundongos , Modelos Moleculares , Transtornos dos Movimentos/fisiopatologia , Mutação , Neurônios/fisiologia , Fosforilação , Ligação Proteica , Ratos , Sinaptossomos/metabolismo , Proteínas rab de Ligação ao GTP/genéticaRESUMO
Parkinson's disease is characterized by intracellular proteinaceous depositions known as Lewy bodies. These largely consist of the protein α-synuclein, whose physiological function remains unclear, but mutations and overexpression of the protein have been shown to cause early onset cases of Parkinson's disease. Deregulation of α-synuclein biology causes neurodegeneration and impaired neuronal trafficking, hinting at a possible contribution to the pathological mechanism. Recent studies produced some evidence hinting at the involvement of several regulators of the transport machinery such as Rab GTPases and SNARE proteins, but also shown that α-synuclein can be propagated between cells. Here, we discuss the molecular interplay of α-synuclein with the intracellular transport machinery, its consequences, and the implications for disease mechanisms.
