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1.
Trends Biochem Sci ; 44(8): 716-728, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31023505

RESUMO

At the turn of this century, cardinal changes took place in the perceptions of the structure and function of proteins, as well as in the organizational principles of membrane-less organelles. As a result, the model of the organization of living matter is changing to one described by highly dynamic biological soft matter positioned at the edge of chaos. Intrinsically disordered proteins (IDPs) and membrane-less organelles are key examples of this new outlook and may represent a critical foundation of life, defining its complexity and the evolution of living things.


Assuntos
Materiais Biocompatíveis/química , Proteínas Intrinsicamente Desordenadas/química , Sequência de Aminoácidos , Transferência Ressonante de Energia de Fluorescência , Organelas/química , Organelas/metabolismo , Transição de Fase , Conformação Proteica , Imagem Individual de Molécula , Temperatura de Transição
2.
EMBO J ; 35(14): 1537-49, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27261198

RESUMO

It is now known that proteins associated with neurodegenerative disease can spread throughout the brain in a prionlike manner. However, the mechanisms regulating the trans-synaptic spread propagation, including the neuronal release of these proteins, remain unknown. The interaction of neurodegenerative disease-associated proteins with the molecular chaperone Hsc70 is well known, and we hypothesized that much like disaggregation, refolding, degradation, and even normal function, Hsc70 may dictate the extracellular fate of these proteins. Here, we show that several proteins, including TDP-43, α-synuclein, and the microtubule-associated protein tau, can be driven out of the cell by an Hsc70 co-chaperone, DnaJC5. In fact, DnaJC5 overexpression induced tau release in cells, neurons, and brain tissue, but only when activity of the chaperone Hsc70 was intact and when tau was able to associate with this chaperone. Moreover, release of tau from neurons was reduced in mice lacking the DnaJC5 gene and when the complement of DnaJs in the cell was altered. These results demonstrate that the dynamics of DnaJ/Hsc70 complexes are critically involved in the release of neurodegenerative disease proteins.


Assuntos
Proteínas de Choque Térmico HSC70/metabolismo , Proteínas de Choque Térmico HSP40/metabolismo , Proteínas de Membrana/metabolismo , Proteínas tau/metabolismo , Linhagem Celular , Proteínas de Ligação a DNA/metabolismo , Humanos , alfa-Sinucleína/metabolismo
3.
PLoS Biol ; 15(6): e2001336, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28654636

RESUMO

The accumulation of amyloidogenic proteins is a pathological hallmark of neurodegenerative disorders. The aberrant accumulation of the microtubule associating protein tau (MAPT, tau) into toxic oligomers and amyloid deposits is a primary pathology in tauopathies, the most common of which is Alzheimer's disease (AD). Intrinsically disordered proteins, like tau, are enriched with proline residues that regulate both secondary structure and aggregation propensity. The orientation of proline residues is regulated by cis/trans peptidyl-prolyl isomerases (PPIases). Here we show that cyclophilin 40 (CyP40), a PPIase, dissolves tau amyloids in vitro. Additionally, CyP40 ameliorated silver-positive and oligomeric tau species in a mouse model of tau accumulation, preserving neuronal health and cognition. Nuclear magnetic resonance (NMR) revealed that CyP40 interacts with tau at sites rich in proline residues. CyP40 was also able to interact with and disaggregate other aggregating proteins that contain prolines. Moreover, CyP40 lacking PPIase activity prevented its capacity for disaggregation in vitro. Finally, we describe a unique structural property of CyP40 that may permit disaggregation to occur in an energy-independent manner. This study identifies a novel human protein disaggregase and, for the first time, demonstrates its capacity to dissolve intracellular amyloids.


Assuntos
Amiloide/metabolismo , Ciclofilinas/metabolismo , Doenças Neurodegenerativas/metabolismo , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Amiloide/genética , Amiloide/ultraestrutura , Animais , Western Blotting , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Transtornos Cognitivos/genética , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/fisiopatologia , Peptidil-Prolil Isomerase F , Ciclofilinas/genética , Ciclosporina/farmacologia , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Masculino , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão , Doenças Neurodegenerativas/genética , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas , Tauopatias/genética , Tauopatias/metabolismo , alfa-Sinucleína/genética , Proteínas tau/genética
4.
Cell Mol Life Sci ; 76(22): 4461-4492, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31428838

RESUMO

GPCR-G protein signaling system recognizes a multitude of extracellular ligands and triggers a variety of intracellular signaling cascades in response. In humans, this system includes more than 800 various GPCRs and a large set of heterotrimeric G proteins. Complexity of this system goes far beyond a multitude of pair-wise ligand-GPCR and GPCR-G protein interactions. In fact, one GPCR can recognize more than one extracellular signal and interact with more than one G protein. Furthermore, one ligand can activate more than one GPCR, and multiple GPCRs can couple to the same G protein. This defines an intricate multifunctionality of this important signaling system. Here, we show that the multifunctionality of GPCR-G protein system represents an illustrative example of the protein structure-function continuum, where structures of the involved proteins represent a complex mosaic of differently folded regions (foldons, non-foldons, unfoldons, semi-foldons, and inducible foldons). The functionality of resulting highly dynamic conformational ensembles is fine-tuned by various post-translational modifications and alternative splicing, and such ensembles can undergo dramatic changes at interaction with their specific partners. In other words, GPCRs and G proteins exist as sets of conformational/basic, inducible/modified, and functioning proteoforms characterized by a broad spectrum of structural features and possessing various functional potentials.


Assuntos
Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/fisiologia , Animais , Humanos , Ligantes , Processamento de Proteína Pós-Traducional/fisiologia
5.
Int J Mol Sci ; 21(15)2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32751642

RESUMO

Misfolding, aggregation and accumulation of proteins are toxic elements in the progression of a broad range of neurodegenerative diseases. Molecular chaperones enable a cellular defense by reducing or compartmentalizing these insults. Small heat shock proteins (sHsps) engage proteins early in the process of misfolding and can facilitate their proper folding or refolding, sequestration, or clearance. Here, we evaluate the effects of the sHsp Hsp22, as well as a pseudophosphorylated mutant and an N-terminal domain deletion (NTDΔ) variant on tau aggregation in vitro and tau accumulation and aggregation in cultured cells. Hsp22 wild-type (WT) protein had a significant inhibitory effect on heparin-induced aggregation in vitro and the pseudophosphorylated mutant Hsp22 demonstrated a similar effect. When co-expressed in a cell culture model with tau, these Hsp22 constructs significantly reduced soluble tau protein levels when transfected at a high ratio relative to tau. However, the Hsp22 NTDΔ protein drastically reduced the soluble protein expression levels of both tau WT and tau P301L/S320F even at lower transfection ratios, which resulted in a correlative reduction of the triton-insoluble tau P301L/S320F aggregates.


Assuntos
Proteínas de Choque Térmico/genética , Chaperonas Moleculares/genética , Doenças Neurodegenerativas/genética , Proteínas tau/genética , Animais , Regulação da Expressão Gênica/genética , Proteínas de Choque Térmico Pequenas/genética , Humanos , Camundongos , Camundongos Transgênicos , Doenças Neurodegenerativas/patologia , Agregação Patológica de Proteínas/genética , Ligação Proteica/genética , Deficiências na Proteostase/genética
6.
Cell Mol Life Sci ; 75(21): 3907-3929, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30066087

RESUMO

Effects of macromolecular crowding on structural and functional properties of ordered proteins, their folding, interactability, and aggregation are well documented. Much less is known about how macromolecular crowding might affect structural and functional behaviour of intrinsically disordered proteins (IDPs) or intrinsically disordered protein regions (IDPRs). To fill this gap, this review represents a systematic analysis of the available literature data on the behaviour of IDPs/IDPRs in crowded environment. Although it was hypothesized that, due to the excluded-volume effects present in crowded environments, IDPs/IDPRs would invariantly fold in the presence of high concentrations of crowding agents or in the crowded cellular environment, accumulated data indicate that, based on their response to the presence of crowders, IDPs/IDPRs can be grouped into three major categories, foldable, non-foldable, and unfoldable. This is because natural cellular environment is not simply characterized by the presence of high concentration of "inert" macromolecules, but represents an active milieu, components of which are engaged in direct physical interactions and soft interactions with target proteins. Some of these interactions with cellular components can cause (local) unfolding of query proteins. In other words, since crowding can cause both folding and unfolding of an IDP or its regions, the outputs of the placing of a query protein to the crowded environment would depend on the balance between these two processes. As a result, and because of the spatio-temporal heterogeneity in structural organization of IDPs, macromolecular crowding can differently affect structures of different IDPs. Recent studies indicate that some IDPs are able to undergo liquid-liquid-phase transitions leading to the formation of various proteinaceous membrane-less organelles (PMLOs). Although interiors of such PMLOs are self-crowded, being characterized by locally increased concentrations of phase-separating IDPs, these IDPs are minimally foldable or even non-foldable at all (at least within the physiologically safe time-frame of normal PMLO existence).


Assuntos
Proteínas Intrinsicamente Desordenadas/química , Substâncias Macromoleculares/química , Conformação Proteica , Dobramento de Proteína , Proteínas Intrinsicamente Desordenadas/genética , Modelos Moleculares , Organelas/química , Organelas/genética
7.
Proteomics ; 18(5-6): e1700193, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29068531

RESUMO

It is recognized now that various proteinaceous membrane-less organelles (PMLOs) are commonly found in cytoplasm, nucleus, and mitochondria of various eukaryotic cells (as well as in the chloroplasts of plant cells). Being different from the "traditional" membrane-encapsulated organelles, such as chloroplasts, endoplasmic reticulum, Golgi apparatus, lysosomes, mitochondria, nucleus, and vacuoles, PMLOs solve the cellular need to facilitate and regulate molecular interactions via reversible and controllable isolation of target molecules in specialized compartments. PMLOs possess liquid-like behavior and are believed to be formed as a result of biological liquid-liquid phase transitions (LLPTs, also known as liquid-liquid phase separation), where an intricate interplay between RNA and intrinsically disordered proteins (IDPs) or hybrid proteins containing ordered domains and intrinsically disordered protein regions (IDPRs) may play an important role. This review analyzes the prevalence of intrinsic disorder in proteins associated with various PMLOs found in human cells and considers some of the functional roles of IDPs/IDPRs in biogenesis of these organelles.


Assuntos
Proteínas Intrinsicamente Desordenadas/metabolismo , Organelas/metabolismo , Humanos , Proteínas Intrinsicamente Desordenadas/química , Modelos Moleculares , Transição de Fase , Conformação Proteica
8.
J Biol Chem ; 291(34): 17897-906, 2016 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-27334923

RESUMO

Single nucleotide polymorphisms in the FKBP5 gene increase the expression of the FKBP51 protein and have been associated with increased risk for neuropsychiatric disorders such as major depression and post-traumatic stress disorder. Moreover, levels of FKBP51 are increased with aging and in Alzheimer disease, potentially contributing to disease pathogenesis. However, aside from its glucocorticoid responsiveness, little is known about what regulates FKBP5 In recent years, non-coding RNAs, and in particular microRNAs, have been shown to modulate disease-related genes and processes. The current study sought to investigate which miRNAs could target and functionally regulate FKBP5 Following in silico data mining and initial target expression validation, miR-511 was found to suppress FKBP5 mRNA and protein levels. Using luciferase p-miR-Report constructs and RNA pulldown assays, we confirmed that miR-511 bound directly to the 3'-UTR of FKBP5, validating the predicted gene-microRNA interaction. miR-511 suppressed glucocorticoid-induced up-regulation of FKBP51 in cells and primary neurons, demonstrating functional, disease-relevant control of the protein. Consistent with a regulator of FKBP5, miR-511 expression in the mouse brain decreased with age but increased following chronic glucocorticoid treatment. Analysis of the predicted target genes of miR-511 revealed that neurogenesis, neuronal development, and neuronal differentiation were likely controlled by these genes. Accordingly, miR-511 increased neuronal differentiation in cells and enhanced neuronal development in primary neurons. Collectively, these findings show that miR-511 is a functional regulator of FKBP5 and can contribute to neuronal differentiation.


Assuntos
Regiões 3' não Traduzidas/fisiologia , Encéfalo/metabolismo , Diferenciação Celular/fisiologia , Regulação da Expressão Gênica/fisiologia , MicroRNAs/metabolismo , Chaperonas Moleculares/biossíntese , Neurogênese/fisiologia , Neurônios/metabolismo , Proteínas de Ligação a Tacrolimo/biossíntese , Animais , Células HeLa , Humanos , Camundongos , MicroRNAs/genética , Chaperonas Moleculares/genética , Proteínas de Ligação a Tacrolimo/genética
9.
Molecules ; 22(12)2017 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-29186753

RESUMO

Intrinsically disordered proteins and proteins with intrinsically disordered regions have been shown to be highly prevalent in disease. Furthermore, disease-causing expansions of the regions containing tandem amino acid repeats often push repetitive proteins towards formation of irreversible aggregates. In fact, in disease-relevant proteins, the increased repeat length often positively correlates with the increased aggregation efficiency and the increased disease severity and penetrance, being negatively correlated with the age of disease onset. The major categories of repeat extensions involved in disease include poly-glutamine and poly-alanine homorepeats, which are often times located in the intrinsically disordered regions, as well as repeats in non-coding regions of genes typically encoding proteins with ordered structures. Repeats in such non-coding regions of genes can be expressed at the mRNA level. Although they can affect the expression levels of encoded proteins, they are not translated as parts of an affected protein and have no effect on its structure. However, in some cases, the repetitive mRNAs can be translated in a non-canonical manner, generating highly repetitive peptides of different length and amino acid composition. The repeat extension-caused aggregation of a repetitive protein may represent a pivotal step for its transformation into a proteotoxic entity that can lead to pathology. The goals of this article are to systematically analyze molecular mechanisms of the proteinopathies caused by the poly-glutamine and poly-alanine homorepeat expansion, as well as by the polypeptides generated as a result of the microsatellite expansions in non-coding gene regions and to examine the related proteins. We also present results of the analysis of the prevalence and functional roles of intrinsic disorder in proteins associated with pathological repeat expansions.


Assuntos
Proteínas Intrinsicamente Desordenadas/metabolismo , Agregação Patológica de Proteínas/metabolismo , Linhagem Celular , Humanos , Proteínas Intrinsicamente Desordenadas/genética , Repetições de Microssatélites , Peptídeos/genética , Peptídeos/metabolismo , Agregados Proteicos , Agregação Patológica de Proteínas/genética , Conformação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
10.
Cell Mol Life Sci ; 72(10): 1863-79, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25666877

RESUMO

Pathological accumulation of the microtubule-associated protein tau, in the form of neurofibrillary tangles, is a major hallmark of Alzheimer's disease, the most prevalent neurodegenerative condition worldwide. In addition to Alzheimer's disease, a number of neurodegenerative diseases, called tauopathies, are characterized by the accumulation of aggregated tau in a variety of brain regions. While tau normally plays an important role in stabilizing the microtubule network of the cytoskeleton, its dissociation from microtubules and eventual aggregation into pathological deposits is an area of intense focus for therapeutic development. Here we discuss the known cellular factors that affect tau aggregation, from post-translational modifications to molecular chaperones.


Assuntos
Doença de Alzheimer/fisiopatologia , Proteínas de Choque Térmico/metabolismo , Chaperonas Moleculares/metabolismo , Agregação Patológica de Proteínas/metabolismo , Proteínas tau/metabolismo , Acetilação , Glicosilação , Humanos , Microtúbulos/metabolismo , Fosforilação , Proteólise , Proteínas tau/genética
11.
ACS Chem Biol ; 18(5): 1124-1135, 2023 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-37144894

RESUMO

The accumulation and aggregation of the microtubule-associated protein tau (tau) into intracellular neuronal tangles are a hallmark of a range of progressive neurodegenerative tauopathies, including Alzheimer's disease (AD), frontotemporal dementia, Pick's disease, and progressive supranuclear palsy. The aberrant phosphorylation of tau is associated with tau aggregates in AD. Members of the heat shock protein 70 kDa (Hsp70) family of chaperones bind directly to tau and modulate tau clearance and aggregation. Small molecules that inhibit the Hsp70 family of chaperones have been shown to reduce the accumulation of tau, including phosphorylated tau. Here, eight analogs of the rhodacyanine inhibitor, JG-98, were synthesized and evaluated. Like JG-98, many of the compounds inhibited ATPase activity of the cytosolic heat shock cognate 70 protein (Hsc70) and reduced total, aggregated, and phosphorylated tau accumulation in cultured cells. Three compounds, representing divergent clogP values, were evaluated for in vivo blood-brain barrier penetration and tau reduction in an ex vivo brain slice model. AL69, the compound with the lowest clogP and the lowest membrane retention in a parallel artificial membrane permeability assay (PAMPA), reduced phosphorylated tau accumulation. Our results suggest that benzothiazole substitutions of JG-98 that increase hydrophilicity may increase the efficacy of these Hsp70 inhibitors to reduce phosphorylated tau.


Assuntos
Doença de Alzheimer , Tauopatias , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Benzotiazóis/farmacologia , Proteínas de Choque Térmico HSP70 , Chaperonas Moleculares , Proteínas tau/metabolismo , Tauopatias/metabolismo
12.
Sci Rep ; 12(1): 7372, 2022 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-35513476

RESUMO

Tau accumulation and progressive loss of neurons are associated with Alzheimer's disease (AD). Aggregation of tau has been associated with endoplasmic reticulum (ER) stress and the activation of the unfolded protein response (UPR). While ER stress and the UPR have been linked to AD, the contribution of these pathways to tau-mediated neuronal death is still unknown. We tested the hypothesis that reducing C/EBP Homologous Protein (CHOP), a UPR induced transcription factor associated with cell death, would mitigate tau-mediated neurotoxicity through the ER stress pathway. To evaluate this, 8.5-month-old male rTg4510 tau transgenic mice were injected with a CHOP-targeting or scramble shRNA AAV9 that also expressed EGFP. Following behavioral assessment, brain tissue was collected at 12 months, when ER stress and neuronal loss is ongoing. No behavioral differences in locomotion, anxiety-like behavior, or learning and memory were found in shCHOP mice. Unexpectedly, mice expressing shCHOP had higher levels of CHOP, which did not affect neuronal count, UPR effector (ATF4), or tau tangles. Overall, this suggests that CHOP is a not a main contributor to neuronal death in rTg4510 mice. Taken together with previous studies, we conclude that ER stress, including CHOP upregulation, does not worsen outcomes in the tauopathic brain.


Assuntos
Doença de Alzheimer , Síndromes Neurotóxicas , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Estresse do Retículo Endoplasmático/genética , Masculino , Camundongos , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , Fatores de Transcrição/metabolismo , Resposta a Proteínas não Dobradas , Regulação para Cima
13.
Biochim Biophys Acta Mol Cell Res ; 1868(5): 118984, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33549703

RESUMO

Protein aggregation is a hallmark of neurodegenerative diseases. However, the mechanism that induces pathogenic aggregation is not well understood. Recently, it has emerged that several of the pathological proteins found in an aggregated or mislocalized state in neurodegenerative diseases are also able to undergo liquid-liquid phase separation (LLPS) under physiological conditions. Although these phase transitions are likely important for various physiological functions, neurodegenerative disease-related mutations and conditions can alter the LLPS behavior of these proteins, which can elicit toxicity. Therefore, therapeutics that antagonize aberrant LLPS may be able to mitigate toxicity and aggregation that is ubiquitous in neurodegenerative disease. Here, we discuss the mechanisms by which aberrant protein phase transitions may contribute to neurodegenerative disease. We also outline potential therapeutic strategies to counter deleterious phases. State without borders: Membrane-less organelles and liquid-liquid phase transitions edited by Vladimir N Uversky.


Assuntos
Mutação , Doenças Neurodegenerativas/metabolismo , Agregação Patológica de Proteínas/genética , Fenômenos Biofísicos , Humanos , Agregados Proteicos , Agregação Patológica de Proteínas/metabolismo
14.
Protein Sci ; 30(7): 1350-1359, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33686711

RESUMO

Alzheimer's disease is a progressive fatal neurodegenerative disease with no cure or effective treatments. The hallmarks of disease include extracellular plaques and intracellular tangles of aggregated protein. The intracellular tangles consist of the microtubule associated protein tau. Preventing the pathological aggregation of tau may be an important therapeutic approach to treat disease. In this study we show that small heat shock protein 22 kDa (Hsp22) can prevent the aggregation of tau in vitro. Additionally, tau can undergo liquid-liquid phase separation (LLPS) in the presence of crowding reagents which causes it to have an increased aggregation rate. We show that Hsp22 can modulate both the aggregation and LLPS behavior of tau in vitro.


Assuntos
Proteínas de Choque Térmico/química , Chaperonas Moleculares/química , Agregados Proteicos , Proteínas tau/química , Humanos
15.
J Clin Invest ; 131(4)2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33586680

RESUMO

Tauopathies display a spectrum of phenotypes from cognitive to affective behavioral impairments; however, mechanisms promoting tau pathology and how tau elicits behavioral impairment remain unclear. We report a unique interaction between polyamine metabolism, behavioral impairment, and tau fate. Polyamines are ubiquitous aliphatic molecules that support neuronal function, axonal integrity, and cognitive processing. Transient increases in polyamine metabolism hallmark the cell's response to various insults, known as the polyamine stress response (PSR). Dysregulation of gene transcripts associated with polyamine metabolism in Alzheimer's disease (AD) brains were observed, and we found that ornithine decarboxylase antizyme inhibitor 2 (AZIN2) increased to the greatest extent. We showed that sustained AZIN2 overexpression elicited a maladaptive PSR in mice with underlying tauopathy (MAPT P301S; PS19). AZIN2 also increased acetylpolyamines, augmented tau deposition, and promoted cognitive and affective behavioral impairments. Higher-order polyamines displaced microtubule-associated tau to facilitate polymerization but also decreased tau seeding and oligomerization. Conversely, acetylpolyamines promoted tau seeding and oligomers. These data suggest that tauopathies launch an altered enzymatic signature that endorses a feed-forward cycle of disease progression. Taken together, the tau-induced PSR affects behavior and disease continuance, but may also position the polyamine pathway as a potential entry point for plausible targets and treatments of tauopathy, including AD.


Assuntos
Doença de Alzheimer/metabolismo , Poliaminas Biogênicas/metabolismo , Carboxiliases/metabolismo , Proteínas de Transporte/metabolismo , Hipocampo/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Carboxiliases/genética , Proteínas de Transporte/genética , Feminino , Hipocampo/patologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Proteínas tau/genética , Proteínas tau/metabolismo
16.
Trends Neurosci ; 43(10): 740-743, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32792144

RESUMO

Amyloid-ß (Aß) accumulation in the brain is a cardinal event in Alzheimer's disease (AD), but the structural basis of Aß-elicited neurotoxicity is unknown. In a recent paper, Ciudad et al. elucidate the first atomic structures of Aß oligomers, which reveal how they form lipid-stabilized pores that might disrupt neuronal membranes and ion homeostasis.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Encéfalo/metabolismo , Humanos , Fragmentos de Peptídeos
17.
Polymers (Basel) ; 11(6)2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31167414

RESUMO

The visible outcome of liquid-liquid phase transitions (LLPTs) in cells is the formation and disintegration of various proteinaceous membrane-less organelles (PMLOs). Although LLPTs and related PMLOs have been observed in living cells for over 200 years, the physiological functions of these transitions (also known as liquid-liquid phase separation, LLPS) are just starting to be understood. While unveiling the functionality of these transitions is important, they have come into light more recently due to the association of abnormal LLPTs with various pathological conditions. In fact, several maladies, such as various cancers, different neurodegenerative diseases, and cardiovascular diseases, are known to be associated with either aberrant LLPTs or some pathological transformations within the resultant PMLOs. Here, we will highlight both the physiological functions of cellular liquid-liquid phase transitions as well as the pathological consequences produced through both dysregulated biogenesis of PMLOs and the loss of their dynamics. We will also discuss the potential downstream toxic effects of proteins that are involved in pathological formations.

18.
Front Pharmacol ; 10: 1047, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31619995

RESUMO

Misfolding, aggregation, and aberrant accumulation of proteins are central components in the progression of neurodegenerative disease. Cellular molecular chaperone systems modulate proteostasis, and, therefore, are primed to influence aberrant protein-induced neurotoxicity and disease progression. Molecular chaperones have a wide range of functions from facilitating proper nascent folding and refolding to degradation or sequestration of misfolded substrates. In disease states, molecular chaperones can display protective or aberrant effects, including the promotion and stabilization of toxic protein aggregates. This seems to be dependent on the aggregating protein and discrete chaperone interaction. Small heat shock proteins (sHsps) are a class of molecular chaperones that typically associate early with misfolded proteins. These interactions hold proteins in a reversible state that helps facilitate refolding or degradation by other chaperones and co-factors. These sHsp interactions require dynamic oligomerization state changes in response to diverse cellular triggers and, unlike later steps in the chaperone cascade of events, are ATP-independent. Here, we review evidence for modulation of neurodegenerative disease-relevant protein aggregation by sHsps. This includes data supporting direct physical interactions and potential roles of sHsps in the stewardship of pathological protein aggregates in brain. A greater understanding of the mechanisms of sHsp chaperone activity may help in the development of novel therapeutic strategies to modulate the aggregation of pathological, amyloidogenic proteins. sHsps-targeting strategies including modulators of expression or post-translational modification of endogenous sHsps, small molecules targeted to sHsp domains, and delivery of engineered molecular chaperones, are also discussed.

19.
Int J Biol Macromol ; 127: 136-145, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30639592

RESUMO

A microsatellite expansion mutation in C9orf72 is the most common genetic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). The expansion mutation leads to C9orf72 loss of function, RNA foci formation, and generation of five species of non-AUG RAN translated dipeptide repeat proteins (DPRs), such as poly(GA), poly(GP), poly(GR), poly(PA), and poly(PR). Although one cell can contain more than type of DPRs, information about interplay between different DPR species is limited. Here we show that the combined expression of distinct C9orf72-derived dipeptide repeat species produces cellular outcomes and structural differences that are unique compared to the expression of a single DPR species, suggesting the complex biological interactions that occur when multiple DPR variants are simultaneously expressed. Our data highlights the need for further analysis of how combined expression of different DPRs affects the disease state.


Assuntos
Esclerose Lateral Amiotrófica , Proteína C9orf72 , Dipeptídeos , Demência Frontotemporal , Sequências Repetitivas de Aminoácidos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Linhagem Celular , Dipeptídeos/genética , Dipeptídeos/metabolismo , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Humanos
20.
Alzheimers Res Ther ; 11(1): 58, 2019 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-31253191

RESUMO

BACKGROUND: Tau stabilizes microtubules; however, in Alzheimer's disease (AD) and tauopathies, tau becomes hyperphosphorylated, aggregates, and results in neuronal death. Our group recently uncovered a unique interaction between polyamine metabolism and tau fate. Polyamines exert an array of physiological effects that support neuronal function and cognitive processing. Specific stimuli can elicit a polyamine stress response (PSR), resulting in altered central polyamine homeostasis. Evidence suggests that elevations in polyamines following a short-term stressor are beneficial; however, persistent stress and subsequent PSR activation may lead to maladaptive polyamine dysregulation, which is observed in AD, and may contribute to neuropathology and disease progression. METHODS: Male and female mice harboring tau P301L mutation (rTg4510) were examined for a tau-induced central polyamine stress response (tau-PSR). The direct effect of tau-PSR byproducts on tau fibrillization and oligomerization were measured using a thioflavin T assay and a N2a split superfolder GFP-Tau (N2a-ssGT) cell line, respectively. To therapeutically target the tau-PSR, we bilaterally injected caspase 3-cleaved tau truncated at aspartate 421 (AAV9 Tau ΔD421) into the hippocampus and cortex of spermidine/spermine-N1-acetyltransferase (SSAT), a key regulator of the tau-PSR, knock out (SSAT-/-), and wild type littermates, and the effects on tau neuropathology, polyamine dysregulation, and behavior were measured. Lastly, cellular models were employed to further examine how SSAT repression impacted tau biology. RESULTS: Tau induced a unique tau-PSR signature in rTg4510 mice, notably in the accumulation of acetylated spermidine. In vitro, higher-order polyamines prevented tau fibrillization but acetylated spermidine failed to mimic this effect and even promoted fibrillization and oligomerization. AAV9 Tau ΔD421 also elicited a unique tau-PSR in vivo, and targeted disruption of SSAT prevented the accumulation of acetylated polyamines and impacted several tau phospho-epitopes. Interestingly, SSAT knockout mice presented with altered behavior in the rotarod task, the elevated plus maze, and marble burying task, thus highlighting the impact of polyamine homeostasis within the brain. CONCLUSION: These data represent a novel paradigm linking tau pathology and polyamine dysfunction and that targeting specific arms within the polyamine pathway may serve as new targets to mitigate certain components of the tau phenotype.


Assuntos
Acetiltransferases/metabolismo , Poliaminas/metabolismo , Estresse Fisiológico , Tauopatias/enzimologia , Acetiltransferases/genética , Animais , Feminino , Hipocampo/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Agregação Patológica de Proteínas/metabolismo , Proteínas tau/metabolismo
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