RESUMEN
Progressive supranuclear palsy (PSP) is a movement disorder characterized by tau neuropathology where the underlying mechanism is unknown. An SNP (rs1768208 C/T) has been identified as a strong risk factor for PSP. Here, we identified a much higher T-allele occurrence and increased levels of the pro-apoptotic protein appoptosin in PSP patients. Elevations in appoptosin correlate with activated caspase-3 and caspase-cleaved tau levels. Appoptosin overexpression increased caspase-mediated tau cleavage, tau aggregation, and synaptic dysfunction, whereas appoptosin deficiency reduced tau cleavage and aggregation. Appoptosin transduction impaired multiple motor functions and exacerbated neuropathology in tau-transgenic mice in a manner dependent on caspase-3 and tau. Increased appoptosin and caspase-3-cleaved tau were also observed in brain samples of patients with Alzheimer's disease and frontotemporal dementia with tau inclusions. Our findings reveal a novel role for appoptosin in neurological disorders with tau neuropathology, linking caspase-3-mediated tau cleavage to synaptic dysfunction and behavioral/motor defects.
Asunto(s)
Apoptosis/genética , Caspasa 3/metabolismo , Regulación de la Expresión Génica/genética , Polimorfismo de Nucleótido Simple/genética , Parálisis Supranuclear Progresiva/genética , Proteínas tau/metabolismo , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Caspasa 3/genética , Células Cultivadas , Modelos Animales de Enfermedad , Embrión de Mamíferos , Femenino , Fuerza de la Mano/fisiología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Proteínas de la Mielina/genética , Proteínas de la Mielina/metabolismo , Ratas , Parálisis Supranuclear Progresiva/patología , Parálisis Supranuclear Progresiva/fisiopatología , Proteínas tau/genéticaRESUMEN
TAR DNA binding protein of 43 kDa (TDP-43) has been implicated in the pathogenesis of a broad range of neurodegenerative diseases termed TDP-43 proteinopathies, which encompass a spectrum of diseases ranging from amyotrophic lateral sclerosis to frontotemporal dementia. Pathologically misfolded and aggregated forms of TDP-43 are found in cytoplasmic inclusion bodies of affected neurons in these diseases. The mechanism by which TDP-43 misfolding causes disease is not well-understood. Current hypotheses postulate that the TDP-43 aggregation process plays a major role in pathogenesis. We amplify that hypothesis and suggest that binding of cognate ligands to TDP-43 can stabilize the native functional state of the protein and ameliorate aggregation. We expressed recombinant TDP-43 containing an N-terminal Venus yellow fluorescent protein tag in Escherichia coli and induced its aggregation by altering solvent salt concentrations and examined the extent to which various oligonucleotide molecules affect its aggregation in vitro using aggregation-induced turbidity assays. We show that vYFP-TDP-43 binding to its naturally occurring RNA target that comprises a sequence on the 3'UTR region of its mRNA improves its solubility, suggesting interplay among TDP-43 solubility, oligonucleotide binding, and TDP-43 autoregulation.
