RESUMEN
Despite advances in machine learning-based protein structure prediction, we are still far from fully understanding how proteins fold into their native conformation. The conventional notion that polypeptides fold spontaneously to their biologically active states has gradually been replaced by our understanding that cellular protein folding often requires context-dependent guidance from molecular chaperones in order to avoid misfolding. Misfolded proteins can aggregate into larger structures, such as amyloid fibrils, which perpetuate the misfolding process, creating a self-reinforcing cascade. A surge in amyloid fibril structures has deepened our comprehension of how a single polypeptide sequence can exhibit multiple amyloid conformations, known as polymorphism. The assembly of these polymorphs is not a random process but is influenced by the specific conditions and tissues in which they originate. This observation suggests that, similar to the folding of native proteins, the kinetics of pathological amyloid assembly are modulated by interactions specific to cells and tissues. Here, we review the current understanding of how intrinsic protein conformational propensities are modulated by physiological and pathological interactions in the cell to shape protein misfolding and aggregation pathology.
Asunto(s)
Amiloide , Pliegue de Proteína , Conformación Proteica , Amiloide/metabolismo , Péptidos , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismoRESUMEN
Although complex inflammatory-like alterations are observed around the amyloid plaques of Alzheimer's disease (AD), little is known about the molecular changes and cellular interactions that characterize this response. We investigate here, in an AD mouse model, the transcriptional changes occurring in tissue domains in a 100-µm diameter around amyloid plaques using spatial transcriptomics. We demonstrate early alterations in a gene co-expression network enriched for myelin and oligodendrocyte genes (OLIGs), whereas a multicellular gene co-expression network of plaque-induced genes (PIGs) involving the complement system, oxidative stress, lysosomes, and inflammation is prominent in the later phase of the disease. We confirm the majority of the observed alterations at the cellular level using in situ sequencing on mouse and human brain sections. Genome-wide spatial transcriptomics analysis provides an unprecedented approach to untangle the dysregulated cellular network in the vicinity of pathogenic hallmarks of AD and other brain diseases.
Asunto(s)
Enfermedad de Alzheimer/patología , Análisis de Secuencia de ADN/métodos , Transcriptoma , Enfermedad de Alzheimer/genética , Amiloide/metabolismo , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Proteínas del Sistema Complemento/genética , Proteínas del Sistema Complemento/metabolismo , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Humanos , Lisosomas/genética , Lisosomas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Vaina de Mielina/genética , Vaina de Mielina/metabolismo , Estrés Oxidativo/genéticaRESUMEN
We previously reported that inducing gamma oscillations with a non-invasive light flicker (gamma entrainment using sensory stimulus or GENUS) impacted pathology in the visual cortex of Alzheimer's disease mouse models. Here, we designed auditory tone stimulation that drove gamma frequency neural activity in auditory cortex (AC) and hippocampal CA1. Seven days of auditory GENUS improved spatial and recognition memory and reduced amyloid in AC and hippocampus of 5XFAD mice. Changes in activation responses were evident in microglia, astrocytes, and vasculature. Auditory GENUS also reduced phosphorylated tau in the P301S tauopathy model. Furthermore, combined auditory and visual GENUS, but not either alone, produced microglial-clustering responses, and decreased amyloid in medial prefrontal cortex. Whole brain analysis using SHIELD revealed widespread reduction of amyloid plaques throughout neocortex after multi-sensory GENUS. Thus, GENUS can be achieved through multiple sensory modalities with wide-ranging effects across multiple brain areas to improve cognitive function.
Asunto(s)
Estimulación Acústica/métodos , Enfermedad de Alzheimer/terapia , Cognición/fisiología , Enfermedad de Alzheimer/patología , Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Percepción Auditiva/fisiología , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Ritmo Gamma/fisiología , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Placa Amiloide/metabolismoRESUMEN
The majority of protein molecules must fold into defined three-dimensional structures to acquire functional activity. However, protein chains can adopt a multitude of conformational states, and their biologically active conformation is often only marginally stable. Metastable proteins tend to populate misfolded species that are prone to forming toxic aggregates, including soluble oligomers and fibrillar amyloid deposits, which are linked with neurodegeneration in Alzheimer and Parkinson disease, and many other pathologies. To prevent or regulate protein aggregation, all cells contain an extensive protein homeostasis (or proteostasis) network comprising molecular chaperones and other factors. These defense systems tend to decline during aging, facilitating the manifestation of aggregate deposition diseases. This volume of the Annual Review of Biochemistry contains a set of three articles addressing our current understanding of the structures of pathological protein aggregates and their associated disease mechanisms. These articles also discuss recent insights into the strategies cells have evolved to neutralize toxic aggregates by sequestering them in specific cellular locations.
Asunto(s)
Envejecimiento/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Parkinson/metabolismo , Agregación Patológica de Proteínas/metabolismo , Deficiencias en la Proteostasis/metabolismo , Envejecimiento/genética , Envejecimiento/patología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Amiloide/química , Amiloide/genética , Amiloide/metabolismo , Regulación de la Expresión Génica , Humanos , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Agregación Patológica de Proteínas/genética , Agregación Patológica de Proteínas/patología , Conformación Proteica , Pliegue de Proteína , Deficiencias en la Proteostasis/genética , Deficiencias en la Proteostasis/patologíaRESUMEN
Peptides and proteins have been found to possess an inherent tendency to convert from their native functional states into intractable amyloid aggregates. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidoses. In this review, we describe this field of science with particular reference to the advances that have been made over the last decade in our understanding of its fundamental nature and consequences. We list the proteins that are known to be deposited as amyloid or other types of aggregates in human tissues and the disorders with which they are associated, as well as the proteins that exploit the amyloid motif to play specific functional roles in humans. In addition, we summarize the genetic factors that have provided insight into the mechanisms of disease onset. We describe recent advances in our knowledge of the structures of amyloid fibrils and their oligomeric precursors and of the mechanisms by which they are formed and proliferate to generate cellular dysfunction. We show evidence that a complex proteostasis network actively combats protein aggregation and that such an efficient system can fail in some circumstances and give rise to disease. Finally, we anticipate the development of novel therapeutic strategies with which to prevent or treat these highly debilitating and currently incurable conditions.
Asunto(s)
Enfermedad de Alzheimer/historia , Amiloide/química , Amiloidosis/historia , Diabetes Mellitus Tipo 2/historia , Enfermedad de Parkinson/historia , Deficiencias en la Proteostasis/historia , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Amiloide/genética , Amiloide/metabolismo , Amiloidosis/tratamiento farmacológico , Amiloidosis/metabolismo , Amiloidosis/patología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Drogas en Investigación , Regulación de la Expresión Génica , Historia del Siglo XXI , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Terapia Molecular Dirigida , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Agregación Patológica de Proteínas/historia , Agregación Patológica de Proteínas/metabolismo , Agregación Patológica de Proteínas/patología , Agregación Patológica de Proteínas/prevención & control , Conformación Proteica , Pliegue de Proteína , Deficiencias en la Proteostasis/tratamiento farmacológico , Deficiencias en la Proteostasis/metabolismo , Deficiencias en la Proteostasis/patología , Deficiencias en la Proteostasis/prevención & controlRESUMEN
Protein conformational states-from intrinsically disordered ensembles to amyloids that underlie the self-templating, infectious properties of prion-like proteins-have attracted much attention. Here, we highlight the diversity, including differences in biophysical properties, that drive distinct biological functions and pathologies among self-templating proteins. Advances in chemical genomics, gene editing, and model systems now permit deconstruction of the complex interplay between these protein states and the host factors that react to them. These methods reveal that conformational switches modulate normal and abnormal information transfer and that intimate relationships exist between the intrinsic function of proteins and the deleterious consequences of their misfolding.
Asunto(s)
Priones/química , Conformación Proteica , Amiloide/química , Amiloide/metabolismo , Animales , Humanos , Modelos Animales , Enfermedades Neurodegenerativas/metabolismo , Priones/metabolismo , Saccharomyces cerevisiae/metabolismoRESUMEN
Aggregation of proteins containing expanded polyglutamine (polyQ) repeats is the cytopathologic hallmark of a group of dominantly inherited neurodegenerative diseases, including Huntington's disease (HD). Huntingtin (Htt), the disease protein of HD, forms amyloid-like fibrils by liquid-to-solid phase transition. Macroautophagy has been proposed to clear polyQ aggregates, but the efficiency of aggrephagy is limited. Here, we used cryo-electron tomography to visualize the interactions of autophagosomes with polyQ aggregates in cultured cells in situ. We found that an amorphous aggregate phase exists next to the radially organized polyQ fibrils. Autophagosomes preferentially engulfed this amorphous material, mediated by interactions between the autophagy receptor p62/SQSTM1 and the non-fibrillar aggregate surface. In contrast, amyloid fibrils excluded p62 and evaded clearance, resulting in trapping of autophagic structures. These results suggest that the limited efficiency of autophagy in clearing polyQ aggregates is due to the inability of autophagosomes to interact productively with the non-deformable, fibrillar disease aggregates.
Asunto(s)
Amiloide , Autofagosomas , Autofagia , Proteína Huntingtina , Enfermedad de Huntington , Péptidos , Agregado de Proteínas , Proteína Sequestosoma-1 , Péptidos/metabolismo , Péptidos/química , Péptidos/genética , Humanos , Proteína Huntingtina/metabolismo , Proteína Huntingtina/genética , Proteína Huntingtina/química , Autofagosomas/metabolismo , Autofagosomas/ultraestructura , Proteína Sequestosoma-1/metabolismo , Proteína Sequestosoma-1/genética , Amiloide/metabolismo , Amiloide/química , Amiloide/genética , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/genética , Enfermedad de Huntington/patología , Microscopía por Crioelectrón , Animales , Agregación Patológica de Proteínas/metabolismo , Agregación Patológica de Proteínas/genéticaRESUMEN
Lung endothelia in the arteries, capillaries, and veins are heterogeneous in structure and function. Lung capillaries in particular represent a unique vascular niche, with a thin yet highly restrictive alveolar-capillary barrier that optimizes gas exchange. Capillary endothelium surveys the blood while simultaneously interpreting cues initiated within the alveolus and communicated via immediately adjacent type I and type II epithelial cells, fibroblasts, and pericytes. This cell-cell communication is necessary to coordinate the immune response to lower respiratory tract infection. Recent discoveries identify an important role for the microtubule-associated protein tau that is expressed in lung capillary endothelia in the host-pathogen interaction. This endothelial tau stabilizes microtubules necessary for barrier integrity, yet infection drives production of cytotoxic tau variants that are released into the airways and circulation, where they contribute to end-organ dysfunction. Similarly, beta-amyloid is produced during infection. Beta-amyloid has antimicrobial activity, but during infection it can acquire cytotoxic activity that is deleterious to the host. The production and function of these cytotoxic tau and amyloid variants are the subject of this review. Lung-derived cytotoxic tau and amyloid variants are a recently discovered mechanism of end-organ dysfunction, including neurocognitive dysfunction, during and in the aftermath of infection.
Asunto(s)
Pulmón , Insuficiencia Multiorgánica , Humanos , Insuficiencia Multiorgánica/metabolismo , Pulmón/metabolismo , Endotelio Vascular/metabolismo , Amiloide/química , Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismoRESUMEN
We here attempt to achieve an integrated understanding of the structure and dynamics of a number of higher-order assemblies, including amyloids, various kinds of signalosomes, and cellular granules. We propose that the synergy between folded domains, linear motifs, and intrinsically disordered regions regulates the formation and intrinsic fuzziness of all higher-order assemblies, creating a structural and dynamic continuum. We describe how such regulatory mechanisms could be influenced under pathological conditions.
Asunto(s)
Orgánulos/química , Orgánulos/metabolismo , Amiloide/química , Amiloide/metabolismo , Humanos , Complejos Multiproteicos/química , Priones/química , Priones/metabolismo , Estructura Cuaternaria de Proteína , Transducción de SeñalRESUMEN
Most vertebrate oocytes contain a Balbiani body, a large, non-membrane-bound compartment packed with RNA, mitochondria, and other organelles. Little is known about this compartment, though it specifies germline identity in many non-mammalian vertebrates. We show Xvelo, a disordered protein with an N-terminal prion-like domain, is an abundant constituent of Xenopus Balbiani bodies. Disruption of the prion-like domain of Xvelo, or substitution with a prion-like domain from an unrelated protein, interferes with its incorporation into Balbiani bodies in vivo. Recombinant Xvelo forms amyloid-like networks in vitro. Amyloid-like assemblies of Xvelo recruit both RNA and mitochondria in binding assays. We propose that Xenopus Balbiani bodies form by amyloid-like assembly of Xvelo, accompanied by co-recruitment of mitochondria and RNA. Prion-like domains are found in germ plasm organizing proteins in other species, suggesting that Balbiani body formation by amyloid-like assembly could be a conserved mechanism that helps oocytes function as long-lived germ cells.
Asunto(s)
Amiloide/metabolismo , Biogénesis de Organelos , Proteínas de Dominio T Box/metabolismo , Proteínas de Xenopus/metabolismo , Animales , Benzotiazoles , Femenino , Colorantes Fluorescentes , Mitocondrias/metabolismo , Oocitos/citología , Orgánulos/metabolismo , Priones/química , Dominios Proteicos , Transporte de Proteínas , ARN Mensajero/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Células Sf9 , Proteínas de Dominio T Box/química , Proteínas de Dominio T Box/genética , Tiazoles , Proteínas de Xenopus/química , Proteínas de Xenopus/genética , Xenopus laevis , Pez CebraRESUMEN
Prions are a paradigm-shifting mechanism of inheritance in which phenotypes are encoded by self-templating protein conformations rather than nucleic acids. Here, we examine the breadth of protein-based inheritance across the yeast proteome by assessing the ability of nearly every open reading frame (ORF; â¼5,300 ORFs) to induce heritable traits. Transient overexpression of nearly 50 proteins created traits that remained heritable long after their expression returned to normal. These traits were beneficial, had prion-like patterns of inheritance, were common in wild yeasts, and could be transmitted to naive cells with protein alone. Most inducing proteins were not known prions and did not form amyloid. Instead, they are highly enriched in nucleic acid binding proteins with large intrinsically disordered domains that have been widely conserved across evolution. Thus, our data establish a common type of protein-based inheritance through which intrinsically disordered proteins can drive the emergence of new traits and adaptive opportunities.
Asunto(s)
Proteínas Intrínsecamente Desordenadas/metabolismo , Carácter Cuantitativo Heredable , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Amiloide/metabolismo , Evolución Molecular , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas HSP90 de Choque Térmico/genética , Proteínas HSP90 de Choque Térmico/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Proteínas Intrínsecamente Desordenadas/química , Proteínas Intrínsecamente Desordenadas/genética , Sistemas de Lectura Abierta , Priones/química , Priones/metabolismo , Proteoma , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genéticaRESUMEN
As substantial constituents of the multiple myeloma (MM) microenvironment, pro-inflammatory macrophages have emerged as key promoters of disease progression, bone destruction, and immune impairment. We identify beta-2-microglobulin (ß2m) as a driver in initiating inflammation in myeloma-associated macrophages (MAMs). Lysosomal accumulation of phagocytosed ß2m promotes ß2m amyloid aggregation in MAMs, resulting in lysosomal rupture and ultimately production of active interleukin-1ß (IL-1ß) and IL-18. This process depends on activation of the NLRP3 inflammasome after ß2m accumulation, as macrophages from NLRP3-deficient mice lack efficient ß2m-induced IL-1ß production. Moreover, depletion or silencing of ß2m in MM cells abrogates inflammasome activation in a murine MM model. Finally, we demonstrate that disruption of NLRP3 or IL-18 diminishes tumor growth and osteolytic bone destruction normally promoted by ß2m-induced inflammasome signaling. Our results provide mechanistic evidence for ß2m's role as an NLRP3 inflammasome activator during MM pathogenesis. Moreover, inhibition of NLRP3 represents a potential therapeutic approach in MM.
Asunto(s)
Amiloide/metabolismo , Mieloma Múltiple/patología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Macrófagos Asociados a Tumores/metabolismo , Microglobulina beta-2/metabolismo , Animales , Células Cultivadas , Humanos , Inflamación/inmunología , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Lisosomas/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Fagocitosis/inmunología , Transducción de Señal/inmunología , Microambiente Tumoral/inmunología , Macrófagos Asociados a Tumores/inmunología , Microglobulina beta-2/genéticaRESUMEN
The aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. The accumulation and deposition of amyloid fibrils, collectively known as amyloidosis, is associated with many pathological conditions that can be associated with ageing, such as Alzheimer disease, Parkinson disease, type II diabetes and dialysis-related amyloidosis. However, elucidation of the atomic structure of amyloid fibrils formed from their intact protein precursors and how fibril formation relates to disease has remained elusive. Recent advances in structural biology techniques, including cryo-electron microscopy and solid-state NMR spectroscopy, have finally broken this impasse. The first near-atomic-resolution structures of amyloid fibrils formed in vitro, seeded from plaque material and analysed directly ex vivo are now available. The results reveal cross-ß structures that are far more intricate than anticipated. Here, we describe these structures, highlighting their similarities and differences, and the basis for their toxicity. We discuss how amyloid structure may affect the ability of fibrils to spread to different sites in the cell and between organisms in a prion-like manner, along with their roles in disease. These molecular insights will aid in understanding the development and spread of amyloid diseases and are inspiring new strategies for therapeutic intervention.
Asunto(s)
Amiloide/metabolismo , Amiloide/fisiología , Amiloide/ultraestructura , Enfermedad de Alzheimer/fisiopatología , Amiloidosis/fisiopatología , Diabetes Mellitus Tipo 2/fisiopatología , Humanos , Enfermedad de Parkinson/fisiopatología , Placa Amiloide/metabolismo , Placa Amiloide/fisiopatologíaRESUMEN
Stress granules are membrane-less organelles composed of RNA-binding proteins (RBPs) and RNA. Functional impairment of stress granules has been implicated in amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy-diseases that are characterized by fibrillar inclusions of RBPs. Genetic evidence suggests a link between persistent stress granules and the accumulation of pathological inclusions. Here, we demonstrate that the disease-related RBP hnRNPA1 undergoes liquid-liquid phase separation (LLPS) into protein-rich droplets mediated by a low complexity sequence domain (LCD). While the LCD of hnRNPA1 is sufficient to mediate LLPS, the RNA recognition motifs contribute to LLPS in the presence of RNA, giving rise to several mechanisms for regulating assembly. Importantly, while not required for LLPS, fibrillization is enhanced in protein-rich droplets. We suggest that LCD-mediated LLPS contributes to the assembly of stress granules and their liquid properties and provides a mechanistic link between persistent stress granules and fibrillar protein pathology in disease.
Asunto(s)
Gránulos Citoplasmáticos/química , Gránulos Citoplasmáticos/metabolismo , Agregación Patológica de Proteínas/metabolismo , Amiloide/metabolismo , Línea Celular Tumoral , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/metabolismo , Células HeLa , Ribonucleoproteína Nuclear Heterogénea A1 , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/química , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , HumanosRESUMEN
Signaling through RAS/MAP kinase pathway is central to biology. ERK has long been perceived as the only substrate for MEK. Here, we report that HSF1, the master regulator of the proteotoxic stress response, is a new MEK substrate. Beyond mediating cell-environment interactions, the MEK-HSF1 regulation impacts malignancy. In tumor cells, MEK blockade inactivates HSF1 and thereby provokes proteomic chaos, presented as protein destabilization, aggregation, and, strikingly, amyloidogenesis. Unlike their non-transformed counterparts, tumor cells are particularly susceptible to proteomic perturbation and amyloid induction. Amyloidogenesis is tumor suppressive, reducing in vivo melanoma growth and contributing to the potent anti-neoplastic effects of proteotoxic stressors. Our findings unveil a key biological function of the oncogenic RAS-MEK signaling in guarding proteostasis and suppressing amyloidogenesis. Thus, proteomic instability is an intrinsic feature of malignant state, and disrupting the fragile tumor proteostasis to promote amyloidogenesis may be a feasible therapeutic strategy.
Asunto(s)
Amiloide/metabolismo , Proteínas de Unión al ADN/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Neoplasias/metabolismo , Estabilidad Proteica , Factores de Transcripción/metabolismo , Animales , Línea Celular Tumoral , Femenino , Factores de Transcripción del Choque Térmico , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Trasplante de Neoplasias , Fosforilación , Agregado de Proteínas , Proteoma/metabolismo , Trasplante HeterólogoRESUMEN
Intermediate species in the assembly of amyloid filaments are believed to play a central role in neurodegenerative diseases and may constitute important targets for therapeutic intervention1,2. However, structural information about intermediate species has been scarce and the molecular mechanisms by which amyloids assemble remain largely unknown. Here we use time-resolved cryogenic electron microscopy to study the in vitro assembly of recombinant truncated tau (amino acid residues 297-391) into paired helical filaments of Alzheimer's disease or into filaments of chronic traumatic encephalopathy3. We report the formation of a shared first intermediate amyloid filament, with an ordered core comprising residues 302-316. Nuclear magnetic resonance indicates that the same residues adopt rigid, ß-strand-like conformations in monomeric tau. At later time points, the first intermediate amyloid disappears and we observe many different intermediate amyloid filaments, with structures that depend on the reaction conditions. At the end of both assembly reactions, most intermediate amyloids disappear and filaments with the same ordered cores as those from human brains remain. Our results provide structural insights into the processes of primary and secondary nucleation of amyloid assembly, with implications for the design of new therapies.
Asunto(s)
Enfermedad de Alzheimer , Amiloide , Encefalopatía Traumática Crónica , Ovillos Neurofibrilares , Proteínas tau , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Amiloide/química , Amiloide/metabolismo , Amiloide/ultraestructura , Encefalopatía Traumática Crónica/metabolismo , Encefalopatía Traumática Crónica/patología , Microscopía por Crioelectrón , Ovillos Neurofibrilares/química , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/ultraestructura , Proteínas tau/química , Proteínas tau/metabolismo , Proteínas tau/ultraestructura , Resonancia Magnética Nuclear Biomolecular , Conformación Proteica , Factores de TiempoRESUMEN
The glymphatic movement of fluid through the brain removes metabolic waste1-4. Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer's disease5-8. Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer's disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid.
Asunto(s)
Enfermedad de Alzheimer , Amiloide , Encéfalo , Líquido Cefalorraquídeo , Líquido Extracelular , Ritmo Gamma , Sistema Glinfático , Animales , Ratones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/prevención & control , Amiloide/metabolismo , Acuaporina 4/metabolismo , Astrocitos/metabolismo , Encéfalo/citología , Encéfalo/metabolismo , Encéfalo/patología , Líquido Cefalorraquídeo/metabolismo , Modelos Animales de Enfermedad , Líquido Extracelular/metabolismo , Sistema Glinfático/fisiología , Interneuronas/metabolismo , Péptido Intestinal Vasoactivo/metabolismo , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Estimulación EléctricaRESUMEN
Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of dementia after Alzheimer's disease, and is often also associated with motor disorders1. The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins2. In the majority of cases the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterizing different FTLD subtypes3,4. The presence of amyloid filaments and their identities and structures in the remaining approximately 10% of FTLD cases are unknown but are widely believed to be composed of the protein fused in sarcoma (FUS, also known as translocated in liposarcoma). As such, these cases are commonly referred to as FTLD-FUS. Here we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD-FUS. Surprisingly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15, also known as TATA-binding protein-associated factor 2N) rather than of FUS itself. The filament fold is formed from residues 7-99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, both showing upper and lower motor neuron pathology. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.
Asunto(s)
Degeneración Lobar Frontotemporal , Factores Asociados con la Proteína de Unión a TATA , Humanos , Amiloide/química , Amiloide/metabolismo , Amiloide/ultraestructura , Tronco Encefálico/metabolismo , Tronco Encefálico/patología , Microscopía por Crioelectrón , Demencia Frontotemporal/etiología , Demencia Frontotemporal/metabolismo , Demencia Frontotemporal/patología , Degeneración Lobar Frontotemporal/complicaciones , Degeneración Lobar Frontotemporal/metabolismo , Degeneración Lobar Frontotemporal/patología , Corteza Motora/metabolismo , Corteza Motora/patología , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Factores Asociados con la Proteína de Unión a TATA/química , Factores Asociados con la Proteína de Unión a TATA/metabolismo , Factores Asociados con la Proteína de Unión a TATA/ultraestructura , Lóbulo Temporal/metabolismo , Lóbulo Temporal/patologíaRESUMEN
Prions, a self-templating amyloidogenic state of normal cellular proteins such as PrP, have been identified as the basis of a number of disease states, particularly diseases of the nervous system. This finding has led to the notion that protein aggregation, namely prionogenic aggregates and amyloids, is primarily harmful for the organism. However, identification of proteins in a prion-like state that are not harmful and may even be beneficial has begun to change this perception. This review discusses when and how a prion-based protein conformational switch may be utilized to generate a sustained physiological change in response to a transient stimulus.
Asunto(s)
Priones/metabolismo , Amiloide/metabolismo , Animales , Humanos , Agregación Patológica de Proteínas/metabolismo , Conformación ProteicaRESUMEN
The amyloidoses are a group of protein misfolding diseases in which the precursor protein undergoes a conformational change that triggers the formation of amyloid fibrils in different tissues and organs, causing cell death and organ failure. Amyloidoses can be either localized or systemic. In localized amyloidosis, amyloid deposits form at the site of precursor protein synthesis, whereas in systemic amyloidosis, amyloid deposition occurs distant from the site of precursor protein secretion. We review the type of proteins and cells involved and what is known about the complex pathophysiology of these diseases. We focus on light chain amyloidosis to illustrate how biochemical and biophysical studies have led to a deeper understanding of the pathogenesis of this devastating disease. We also review current cellular, tissue, and animal models and discuss the challenges and opportunities for future studies of the systemic amyloidoses.