Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Más filtros

Bases de datos
Tipo del documento
Asunto de la revista
País de afiliación
Intervalo de año de publicación
1.
PLoS Pathog ; 19(9): e1011487, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37747931

RESUMEN

Select prion diseases are characterized by widespread cerebral plaque-like deposits of amyloid fibrils enriched in heparan sulfate (HS), a abundant extracellular matrix component. HS facilitates fibril formation in vitro, yet how HS impacts fibrillar plaque growth within the brain is unclear. Here we found that prion-bound HS chains are highly sulfated, and that the sulfation is essential for accelerating prion conversion in vitro. Using conditional knockout mice to deplete the HS sulfation enzyme, Ndst1 (N-deacetylase / N-sulfotransferase) from neurons or astrocytes, we investigated how reducing HS sulfation impacts survival and prion aggregate distribution during a prion infection. Neuronal Ndst1-depleted mice survived longer and showed fewer and smaller parenchymal plaques, shorter fibrils, and increased vascular amyloid, consistent with enhanced aggregate transit toward perivascular drainage channels. The prolonged survival was strain-dependent, affecting mice infected with extracellular, plaque-forming, but not membrane bound, prions. Live PET imaging revealed rapid clearance of recombinant prion protein monomers into the CSF of neuronal Ndst1- deficient mice, neuronal, further suggesting that HS sulfate groups hinder transit of extracellular prion protein monomers. Our results directly show how a host cofactor slows the spread of prion protein through the extracellular space and identify an enzyme to target to facilitate aggregate clearance.


Asunto(s)
Neuronas , Enfermedades por Prión , Priones , Sulfotransferasas , Animales , Ratones , Heparitina Sulfato/metabolismo , Ratones Noqueados , Neuronas/enzimología , Enfermedades por Prión/metabolismo , Proteínas Priónicas/genética , Priones/metabolismo , Sulfotransferasas/genética , Sulfotransferasas/metabolismo
2.
Acta Neuropathol ; 146(1): 31-50, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37154939

RESUMEN

Tau neurofibrillary tangles are a hallmark of Alzheimer's disease neuropathological change. However, it remains largely unclear how distinctive Alzheimer's disease tau seeds (i.e. 3R/4R) correlate with histological indicators of tau accumulation. Furthermore, AD tau co-pathology is thought to influence features and progression of other neurodegenerative diseases including Lewy body disease; yet measurements of different types of tau seeds in the setting of such diseases is an unmet need. Here, we use tau real-time quaking-induced conversion (RT-QuIC) assays to selectively quantitate 3R/4R tau seeds in the frontal lobe which accumulates histologically identifiable tau pathology at late disease stages of AD neuropathologic change. Seed quantitation across a spectrum of neurodegenerative disease cases and controls indicated tau seeding activity can be detected well before accompanying histopathological indication of tau deposits, and even prior to the earliest evidence of Alzheimer's-related tau accumulation anywhere in the brain. In later stages of AD, 3R/4R tau RT-QuIC measures correlated with immunohistochemical tau burden. In addition, Alzheimer's tau seeds occur in the vast majority of cases evaluated here inclusive of primary synucleinopathies, frontotemporal lobar degeneration and even controls albeit at multi-log lower levels than Alzheimer's cases. α-synuclein seeding activity confirmed synucleinopathy cases and further indicated the co-occurrence of α-synuclein seeds in some Alzheimer's disease and primary tauopathy cases. Our analysis indicates that 3R/4R tau seeds in the mid-frontal lobe correlate with the overall Braak stage and Alzheimer's disease neuropathologic change, supporting the quantitative predictive value of tau RT-QuIC assays. Our data also indicate 3R/4R tau seeds are elevated in females compared to males at high (≥ IV) Braak stages. This study suggests 3R/4R tau seeds are widespread even prior to the earliest stages of Alzheimer's disease changes, including in normal, and even young individuals, with prevalence across multiple neurodegenerative diseases to further define disease subtypes.


Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Sinucleinopatías , Tauopatías , Femenino , Humanos , Masculino , alfa-Sinucleína , Enfermedad de Alzheimer/patología , Proteínas tau , Tauopatías/patología
3.
Nat Commun ; 13(1): 4005, 2022 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-35831291

RESUMEN

Little is known about the structural basis of prion strains. Here we provide a high (3.0 Å) resolution cryo-electron microscopy-based structure of infectious brain-derived fibrils of the mouse anchorless RML scrapie strain which, like the recently determined hamster 263K strain, has a parallel in-register ß-sheet-based core. Several structural motifs are shared between these ex vivo prion strains, including an amino-proximal steric zipper and three ß-arches. However, detailed comparisons reveal variations in these shared structural topologies and other features. Unlike 263K and wildtype RML prions, the anchorless RML prions lack glycophosphatidylinositol anchors and are severely deficient in N-linked glycans. Nonetheless, the similarity of our anchorless RML structure to one reported for wildtype RML prion fibrils in an accompanying paper indicates that these post-translational modifications do not substantially alter the amyloid core conformation. This work demonstrates both common and divergent structural features of prion strains at the near-atomic level.


Asunto(s)
Priones , Scrapie , Amiloide , Animales , Encéfalo/metabolismo , Microscopía por Crioelectrón , Ratones , Priones/metabolismo , Ovinos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA