RESUMO
Polyphosphate (polyP), a several billion-year-old biopolymer, is produced in every cell, tissue, and organism studied. Structurally extremely simple, polyP consists of long chains of covalently linked inorganic phosphate groups. We report here the surprising discovery that polyP shows a remarkable efficacy in accelerating amyloid fibril formation. We found that polyP serves as an effective nucleation source for various different amyloid proteins, ranging from bacterial CsgA to human α-synuclein, Aß1-40/42, and Tau. polyP-associated α-synuclein fibrils show distinct differences in seeding behavior, morphology, and fibril stability compared with fibrils formed in the absence of polyP. In vivo, the amyloid-stimulating and fibril-stabilizing effects of polyP have wide-reaching consequences, increasing the rate of biofilm formation in pathogenic bacteria and mitigating amyloid toxicity in differentiated neuroblastoma cells and C. elegans strains that serve as models for human folding diseases. These results suggest that we have discovered a conserved cytoprotective modifier of amyloidogenic processes.
Assuntos
Peptídeos beta-Amiloides/agonistas , Proteínas de Escherichia coli/agonistas , Fragmentos de Peptídeos/agonistas , Polifosfatos/farmacologia , alfa-Sinucleína/agonistas , Proteínas tau/agonistas , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Animais Geneticamente Modificados , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Linhagem Celular Tumoral , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Expressão Gênica , Humanos , Cinética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Polifosfatos/química , Dobramento de Proteína/efeitos dos fármacos , alfa-Sinucleína/química , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Proteínas tau/química , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Folate deficiency and hypomethylation have been implicated in a number of age-related neurodegenerative disorders including dementia and Parkinson's disease (PD). Levodopa (L-dopa) therapy in PD patients has been shown to cause an increase in plasma total homocysteine as well as depleting cellular concentrations of the methyl donor, S-adenosylmethionine (SAM), and increasing the demethylated product S-adenosylhomocysteine (SAH). Modulation of the cellular SAM/SAH ratio can influence activity of methyltransferase enzymes, including leucine carboxyl methyltransferase that specifically methylates Ser/Thr protein phosphatase 2A (PP2A), a major Tau phosphatase. Here we show in human SH-SY5Y cells, in dopaminergic neurons, and in wild-type mice that l-dopa results in a reduced SAM/SAH ratio that is associated with hypomethylation of PP2A and increased phosphorylation of Tau (p-Tau) at the Alzheimer's disease-like PHF-1 phospho-epitope. The effect of L-dopa on PP2A and p-Tau was exacerbated in cells exposed to folate deficiency. In the folate-deficient mouse model, L-dopa resulted in a marked depletion of SAM and an increase in SAH in various brain regions with parallel downregulation of PP2A methylation and increased Tau phosphorylation. L-Dopa also enhanced demethylated PP2A amounts in the liver. These findings reveal a novel mechanism involving methylation-dependent pathways in L-dopa induces PP2A hypomethylation and increases Tau phosphorylation, which may be potentially detrimental to neuronal cells.
Assuntos
Encéfalo/metabolismo , Neurônios Dopaminérgicos/enzimologia , Levodopa/toxicidade , Degeneração Neural/metabolismo , Proteína Fosfatase 2/metabolismo , Proteínas tau/metabolismo , Animais , Antiparkinsonianos/toxicidade , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Linhagem Celular Tumoral , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Masculino , Metilação/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Degeneração Neural/induzido quimicamente , Degeneração Neural/fisiopatologia , Neuroblastoma , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Cultura Primária de Células , Proteína Fosfatase 2/antagonistas & inibidores , Proteínas tau/agonistas , Proteínas tau/biossínteseRESUMO
Existing treatments for Alzheimer's disease (AD) fail to address the underlying pathology of the disease; they merely provide short-lived symptomatic relief. Consequently, the progression of AD is unrelenting, leading to a continual decrease in cognitive abilities. Recent advances in understanding the genetic factors that predispose to AD, as well as in biomarker development, have brought with them the promise of earlier and more reliable diagnosis of this disease. As improvements continue to be made in these areas, the shortcomings of current AD treatments appear all the more acute because opportunities for early intervention are hindered by a lack of "curative" or even disease-modifying drugs. This State of the Art report reviews existing AD therapeutics and highlights recent progress made in the design and development of drugs that are aimed at disrupting AD disease progression by inhibition of the protein misfolding of ß-amyloid (Aß) into neurotoxic oligomeric aggregates.