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1.
Adv Exp Med Biol ; 1325: 137-149, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34495533

RESUMO

Extracellular vesicles (EVs), a generic term for any vesicles or particles that are released from cells, play an important role in modulating numerous biological and pathological events, including development, differentiation, aging, thrombus formation, immune responses, neurodegenerative diseases, and tumor progression. During the biogenesis of EVs, they encapsulate biologically active macromolecules (i.e., nucleotides and proteins) and transmit signals for delivering them to neighboring or cells that are located some distance away. In contrast, there are receptor molecules on the surface of EVs that function to mediate EV-to-cell and EV-to-matrix interactions. A growing body of evidence indicates that the EV surface is heavily modified with glycans, the function of which is to regulate the biogenesis and extracellular behaviors of EVs. In this chapter, we introduce the current status of our knowledge concerning EV glycosylation and discuss how it influences EV biology, highlighting the potential roles of EV glycans in clinical applications.


Assuntos
Exossomos , Vesículas Extracelulares , Doenças Neurodegenerativas , Exossomos/metabolismo , Vesículas Extracelulares/metabolismo , Glicosilação , Humanos , Doenças Neurodegenerativas/metabolismo
2.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360909

RESUMO

Neurodegenerative diseases are an ever-increasing problem for the rapidly aging population. Despite this, our understanding of how these neurodegenerative diseases develop and progress, is in most cases, rudimentary. Protein kinase RNA (PKR)-like ER kinase (PERK) comprises one of three unfolded protein response pathways in which cells attempt to manage cellular stress. However, because of its role in the cellular stress response and the far-reaching implications of this pathway, error within the PERK pathway has been shown to lead to a variety of pathologies. Genetic and clinical studies show a correlation between failure of the PERK pathway in neural cells and the development of neurodegeneration, but the wide array of methodology of these studies is presenting conflicting narratives about the role of PERK in these affected systems. Because of the connection between PERK and pathology, PERK has become a high value target of study for understanding neurodegenerative diseases and potentially how to treat them. Here, we present a review of the literature indexed in PubMed of the PERK pathway and some of the complexities involved in investigating the protein's role in the development of neurodegenerative diseases as well as how it may act as a target for therapeutics.


Assuntos
Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Transdução de Sinais/genética , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo , Idoso , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular/métodos , Doenças Neurodegenerativas/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Transdução de Sinais/efeitos dos fármacos , Resposta a Proteínas não Dobradas , eIF-2 Quinase/antagonistas & inibidores
3.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445804

RESUMO

Protein kinases (PKs) have been recognized as central nervous system (CNS)-disease-relevant targets due to their master regulatory role in different signal transduction cascades in the neuroscience space. Among them, GSK-3ß, FYN, and DYRK1A play a crucial role in the neurodegeneration context, and the deregulation of all three PKs has been linked to different CNS disorders with unmet medical needs, including Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and several neuromuscular disorders. The multifactorial nature of these diseases, along with the failure of many advanced CNS clinical trials, and the lengthy approval process of a novel CNS drug have strongly limited the CNS drug discovery. However, in the near-decade from 2010 to 2020, several computer-assisted drug design strategies have been combined with synthetic efforts to develop potent and selective GSK-3ß, FYN, and DYRK1A inhibitors as disease-modifying agents. In this review, we described both structural and functional aspects of GSK-3ß, FYN, and DYRK1A and their involvement and crosstalk in different CNS pathological signaling pathways. Moreover, we outlined attractive medicinal chemistry approaches including multi-target drug design strategies applied to overcome some limitations of known PKs inhibitors and discover improved modulators with suitable blood-brain barrier (BBB) permeability and drug-like properties.


Assuntos
Glicogênio Sintase Quinase 3 beta/metabolismo , Doenças Neurodegenerativas/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Transdução de Sinais/fisiologia , Animais , Humanos
5.
FASEB J ; 35(9): e21810, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34390520

RESUMO

Copper (Cu) is an essential micronutrient required for the activity of redox-active enzymes involved in critical metabolic reactions, signaling pathways, and biological functions. Transporters and chaperones control Cu ion levels and bioavailability to ensure proper subcellular and systemic Cu distribution. Intensive research has focused on understanding how mammalian cells maintain Cu homeostasis, and how molecular signals coordinate Cu acquisition and storage within organs. In humans, mutations of genes that regulate Cu homeostasis or facilitate interactions with Cu ions lead to numerous pathologic conditions. Malfunctions of the Cu+ -transporting ATPases ATP7A and ATP7B cause Menkes disease and Wilson disease, respectively. Additionally, defects in the mitochondrial and cellular distributions and homeostasis of Cu lead to severe neurodegenerative conditions, mitochondrial myopathies, and metabolic diseases. Cu has a dual nature in carcinogenesis as a promotor of tumor growth and an inducer of redox stress in cancer cells. Cu also plays role in cancer treatment as a component of drugs and a regulator of drug sensitivity and uptake. In this review, we provide an overview of the current knowledge of Cu metabolism and transport and its relation to various human pathologies.


Assuntos
Cobre/metabolismo , Homeostase/fisiologia , Animais , Transporte Biológico/fisiologia , ATPases Transportadoras de Cobre/metabolismo , Humanos , Doenças Metabólicas/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Neurodegenerativas/metabolismo
6.
Nat Commun ; 12(1): 4863, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381050

RESUMO

Spreading of aggregate pathology across brain regions acts as a driver of disease progression in Tau-related neurodegeneration, including Alzheimer's disease (AD) and frontotemporal dementia. Aggregate seeds released from affected cells are internalized by naïve cells and induce the prion-like templating of soluble Tau into neurotoxic aggregates. Here we show in a cellular model system and in neurons that Clusterin, an abundant extracellular chaperone, strongly enhances Tau aggregate seeding. Upon interaction with Tau aggregates, Clusterin stabilizes highly potent, soluble seed species. Tau/Clusterin complexes enter recipient cells via endocytosis and compromise the endolysosomal compartment, allowing transfer to the cytosol where they propagate aggregation of endogenous Tau. Thus, upregulation of Clusterin, as observed in AD patients, may enhance Tau seeding and possibly accelerate the spreading of Tau pathology.


Assuntos
Clusterina/metabolismo , Agregação Patológica de Proteínas/metabolismo , Proteínas tau/metabolismo , Animais , Clusterina/genética , Progressão da Doença , Endocitose , Humanos , Camundongos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurônios/metabolismo , Neurônios/patologia , Agregação Patológica de Proteínas/patologia , Ligação Proteica , alfa-Sinucleína/metabolismo , Proteínas tau/genética
8.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360841

RESUMO

Since their discovery, heat shock proteins (HSPs) have been identified in all domains of life, which demonstrates their importance and conserved functional role in maintaining protein homeostasis. Mitochondria possess several members of the major HSP sub-families that perform essential tasks for keeping the organelle in a fully functional and healthy state. In humans, the mitochondrial HSP70 chaperone system comprises a central molecular chaperone, mtHSP70 or mortalin (HSPA9), which is actively involved in stabilizing and importing nuclear gene products and in refolding mitochondrial precursor proteins, and three co-chaperones (HSP70-escort protein 1-HEP1, tumorous imaginal disc protein 1-TID-1, and Gro-P like protein E-GRPE), which regulate and accelerate its protein folding functions. In this review, we summarize the roles of mitochondrial molecular chaperones with particular focus on the human mtHsp70 and its co-chaperones, whose deregulated expression, mutations, and post-translational modifications are often considered to be the main cause of neurological disorders, genetic diseases, and malignant growth.


Assuntos
Proteínas de Choque Térmico HSP70/metabolismo , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Doenças Neurodegenerativas/metabolismo , Proteínas de Choque Térmico HSP70/genética , Humanos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Mutação , Neoplasias/genética , Doenças Neurodegenerativas/genética , Processamento de Proteína Pós-Traducional
9.
Cell Mol Life Sci ; 78(17-18): 6215-6227, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34365521

RESUMO

The IL-36 family of cytokines were first identified in 2000 based on their sequence homology to IL-1 cytokines. Over subsequent years, the ability of these cytokines to either agonise or antagonise an IL-1R homologue, now known as the IL-36 Receptor (IL-36R), was identified and these cytokines went through several cycles of renaming with the current nomenclature being proposed in 2010. Despite being identified over 20 years ago, it is only during the last decade that the function of these cytokines in health and disease has really begun to be appreciated, with both homeostatic functions in wound healing and response to infection, as well as pathological functions now ascribed. In the disease context, over activation of IL-36 has now been associated with many inflammatory diseases including Psoriasis and inflammatory bowel diseases, with roles in cancer also now being investigated. This review summarises the current knowledge of IL-36 biology, its role in inflammatory diseases and focuses on an emerging role for IL-36 in cancer.


Assuntos
Doenças Inflamatórias Intestinais/patologia , Interleucina-1/metabolismo , Neoplasias/patologia , Humanos , Imunidade Inata , Doenças Inflamatórias Intestinais/metabolismo , Interleucina-1/química , Interleucina-1/genética , Interleucinas/genética , Interleucinas/metabolismo , Artropatias/metabolismo , Artropatias/patologia , Neoplasias/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Psoríase/metabolismo , Psoríase/patologia , Transdução de Sinais
10.
Nat Commun ; 12(1): 5040, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413305

RESUMO

SMN is a ubiquitously expressed protein and is essential for life. SMN deficiency causes the neurodegenerative disease spinal muscular atrophy (SMA), the leading genetic cause of infant mortality. SMN interacts with itself and other proteins to form a complex that functions in the assembly of ribonucleoproteins. SMN is modified by SUMO (Small Ubiquitin-like Modifier), but whether sumoylation is required for the functions of SMN that are relevant to SMA pathogenesis is not known. Here, we show that inactivation of a SUMO-interacting motif (SIM) alters SMN sub-cellular distribution, the integrity of its complex, and its function in small nuclear ribonucleoproteins biogenesis. Expression of a SIM-inactivated mutant of SMN in a mouse model of SMA slightly extends survival rate with limited and transient correction of motor deficits. Remarkably, although SIM-inactivated SMN attenuates motor neuron loss and improves neuromuscular junction synapses, it fails to prevent the loss of sensory-motor synapses. These findings suggest that sumoylation is important for proper assembly and function of the SMN complex and that loss of this post-translational modification impairs the ability of SMN to correct selective deficits in the sensory-motor circuit of SMA mice.


Assuntos
Neurônios Motores/metabolismo , Atrofia Muscular Espinal/patologia , Doenças Neurodegenerativas/patologia , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Proteínas do Complexo SMN/metabolismo , Sumoilação , Sinapses/metabolismo , Animais , Animais Geneticamente Modificados , Células Cultivadas , Modelos Animais de Doenças , Humanos , Camundongos , Neurônios Motores/patologia , Atrofia Muscular Espinal/metabolismo , Doenças Neurodegenerativas/metabolismo , Sinapses/patologia , Peixe-Zebra
11.
Neuron ; 109(17): 2663-2681, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34297914

RESUMO

Aggregation of RNA-binding proteins (RBPs) is a pathological hallmark of neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In these diseases, TDP-43 and FUS RBPs are depleted from the nuclear compartment, where they are normally localized, and found within cytoplasmic inclusions in degenerating regions of affected individuals' postmortem tissue. The mechanisms responsible for aggregation of these proteins has remained elusive, but recent studies suggest liquid-liquid phase separation (LLPS) might serve as a critical nucleation step in formation of pathological inclusions. The process of phase separation also underlies the formation and maintenance of several functional membraneless organelles (MLOs) throughout the cell, some of which contain TDP-43, FUS, and other disease-linked RBPs. One common ligand of disease-linked RBPs, RNA, is a major component of MLOs containing RBPs and has been demonstrated to be a strong modulator of RBP phase transitions. Although early evidence suggested a largely synergistic effect of RNA on RBP phase separation and MLO assembly, recent work indicates that RNA can also antagonize RBP phase behavior under certain physiological and pathological conditions. In this review, we describe the mechanisms underlying RNA-mediated phase transitions of RBPs and examine the molecular properties of these interactions, such as RNA length, sequence, and secondary structure, that mediate physiological or pathological LLPS.


Assuntos
Doenças Neurodegenerativas/metabolismo , Dobramento de Proteína , Deficiências na Proteostase/metabolismo , RNA/metabolismo , Animais , Humanos , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo
12.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204228

RESUMO

Regular exercise is associated with pronounced health benefits. The molecular processes involved in physiological adaptations to exercise are best understood in skeletal muscle. Enhanced mitochondrial functions in muscle are central to exercise-induced adaptations. However, regular exercise also benefits the brain and is a major protective factor against neurodegenerative diseases, such as the most common age-related form of dementia, Alzheimer's disease, or the most common neurodegenerative motor disorder, Parkinson's disease. While there is evidence that exercise induces signalling from skeletal muscle to the brain, the mechanistic understanding of the crosstalk along the muscle-brain axis is incompletely understood. Mitochondria in both organs, however, seem to be central players. Here, we provide an overview on the central role of mitochondria in exercise-induced communication routes from muscle to the brain. These routes include circulating factors, such as myokines, the release of which often depends on mitochondria, and possibly direct mitochondrial transfer. On this basis, we examine the reported effects of different modes of exercise on mitochondrial features and highlight their expected benefits with regard to neurodegeneration prevention or mitigation. In addition, knowledge gaps in our current understanding related to the muscle-brain axis in neurodegenerative diseases are outlined.


Assuntos
Encéfalo/metabolismo , Suscetibilidade a Doenças , Músculo Esquelético/metabolismo , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Citocinas/metabolismo , Metabolismo Energético , Exercício Físico , Humanos , Mitocôndrias , Dinâmica Mitocondrial , Doenças Neurodegenerativas/patologia , Neuroproteção , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
13.
Nat Commun ; 12(1): 4272, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34257293

RESUMO

The first exon of the huntingtin protein (HTTex1) important in Huntington's disease (HD) can form cross-ß fibrils of varying toxicity. We find that the difference between these fibrils is the degree of entanglement and dynamics of the C-terminal proline-rich domain (PRD) in a mechanism analogous to polyproline film formation. In contrast to fibril strains found for other cross-ß fibrils, these HTTex1 fibril types can be interconverted. This is because the structure of their polyQ fibril core remains unchanged. Further, we find that more toxic fibrils of low entanglement have higher affinities for protein interactors and are more effective seeds for recombinant HTTex1 and HTTex1 in cells. Together these data show how the structure of a framing sequence at the surface of a fibril can modulate seeding, protein-protein interactions, and thereby toxicity in neurodegenerative disease.


Assuntos
Proteína Huntingtina/metabolismo , Doença de Huntington/metabolismo , Doenças Neurodegenerativas/metabolismo , Humanos , Proteína Huntingtina/genética , Doença de Huntington/genética , Doenças Neurodegenerativas/genética , Peptídeos/química , Peptídeos/metabolismo , Mapas de Interação de Proteínas
14.
J Enzyme Inhib Med Chem ; 36(1): 1679-1693, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34309456

RESUMO

The ageing population is becoming a significant socio-economic issue. To address the expanding health gap, it is important to deepen our understanding of the mechanisms underlying ageing in various organisms at the single-cell level. The discovery of the antifungal, immunosuppressive, and anticancer drug rapamycin, which possesses the ability to extend the lifespan of several species, has prompted extensive research in the areas of cell metabolic regulation, development, and senescence. At the centre of this research is the mTOR pathway, with key roles in cell growth, proteosynthesis, ribosomal biogenesis, transcriptional regulation, glucose and lipid metabolism, and autophagy. Recently, it has become obvious that mTOR dysregulation is involved in several age-related diseases, such as cancer, neurodegenerative diseases, and type 2 diabetes mellitus. Additionally, mTOR hyperactivation affects the process of ageing per se. In this review, we provide an overview of recent insights into the mTOR signalling pathway, including its regulation and its influence on various hallmarks of ageing at the cellular level.


Assuntos
Neoplasias/metabolismo , Doenças Neurodegenerativas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fatores Etários , Animais , Humanos , Transdução de Sinais
15.
Adv Clin Chem ; 103: 97-134, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34229853

RESUMO

Neurodegenerative diseases are a heterogeneous group of disorders characterized by gradual progressive neuronal loss in the central nervous system. Unfortunately, the pathogenesis of many of these diseases remains unknown. Synucleins are a family of small, highly charged proteins expressed predominantly in neurons. Following their discovery, much has been learned about their structure, function, interaction with other proteins and role in neurodegenerative disease over the last two decades. One of these proteins, α-Synuclein (α-Syn), appears to be involved in many neurodegenerative disorders. These include Parkinson's disease (PD), dementia with Lewy bodies (DLB), Rapid Eye Movement Sleep Behavior Disorder (RBD) and Pure Autonomic Failure (PAF), i.e., collectively termed α-synucleinopathies. This review focuses on α-Syn dysfunction in neurodegeneration and assesses its role in synucleinopathies from a biochemical, genetic and neuroimaging perspective.


Assuntos
Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Sinucleínas/metabolismo , Biomarcadores/metabolismo , Regulação da Expressão Gênica , Humanos , Doenças Neurodegenerativas/genética , Sinucleínas/genética
16.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299185

RESUMO

Nervous system development involves proliferation and cell specification of progenitor cells into neurons and glial cells. Unveiling how this complex process is orchestrated under physiological conditions and deciphering the molecular and cellular changes leading to neurological diseases is mandatory. To date, great efforts have been aimed at identifying gene mutations associated with many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Mutations in the RNA/DNA binding protein Fused in Sarcoma/Translocated in Liposarcoma (FUS/TLS) have been associated with motor neuron degeneration in rodents and humans. Furthermore, increased levels of the wild-type protein can promote neuronal cell death. Despite the well-established causal link between FUS mutations and ALS, its role in neural cells remains elusive. In order to shed new light on FUS functions we studied its role in the control of neural stem progenitor cell (NSPC) properties. Here, we report that human wild-type Fused in Sarcoma (WT FUS), exogenously expressed in mouse embryonic spinal cord-derived NSPCs, was localized in the nucleus, caused cell cycle arrest in G1 phase by affecting cell cycle regulator expression, and strongly reduced neuronal differentiation. Furthermore, the expression of the human mutant form of FUS (P525L-FUS), associated with early-onset ALS, drives the cells preferentially towards a glial lineage, strongly reducing the number of developing neurons. These results provide insight into the involvement of FUS in NSPC proliferation and differentiation into neurons and glia.


Assuntos
Mutação , Células-Tronco Neurais/citologia , Neuroglia/citologia , Neurônios/patologia , Proteína FUS de Ligação a RNA/metabolismo , Medula Espinal/citologia , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Animais , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Camundongos , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/metabolismo , Proteína FUS de Ligação a RNA/genética , Medula Espinal/embriologia , Medula Espinal/metabolismo , Medula Espinal/patologia
17.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281203

RESUMO

Understanding the molecular mechanisms underlying the pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, is a major challenge. We used co-expression networks implemented by the SWitch Miner software to identify switch genes associated with drastic transcriptomic changes in the blood of ALS patients. Functional analyses revealed that switch genes were enriched in pathways related to the cell cycle, hepatitis C, and small cell lung cancer. Analysis of switch genes by sex revealed that switch genes from males were associated with metabolic pathways, including PI3K-AKT, sphingolipid, carbon metabolism, FOXO, and AMPK signaling. In contrast, female switch genes related to infectious diseases, inflammation, apoptosis, and atherosclerosis. Furthermore, eight switch genes showed sex-specific gene expression patterns. Collectively, we identified essential genes and pathways that may explain sex differences observed in ALS. Future studies investigating the potential role of these genes in driving disease disparities between males and females with ALS are warranted.


Assuntos
Esclerose Amiotrófica Lateral/genética , Redes Reguladoras de Genes , Adulto , Esclerose Amiotrófica Lateral/sangue , Esclerose Amiotrófica Lateral/metabolismo , Feminino , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Caracteres Sexuais , Fatores Sexuais , Transdução de Sinais , Transcriptoma
18.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207360

RESUMO

Discoidin domain receptor (DDR) is a collagen-activated receptor tyrosine kinase that plays critical roles in regulating essential cellular processes such as morphogenesis, differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. As a result, DDR dysregulation has been attributed to a variety of human cancer disorders, for instance, non-small-cell lung carcinoma (NSCLC), ovarian cancer, glioblastoma, and breast cancer, in addition to some inflammatory and neurodegenerative disorders. Since the target identification in the early 1990s to date, a lot of efforts have been devoted to the development of DDR inhibitors. From a medicinal chemistry perspective, we attempted to reveal the progress in the development of the most promising DDR1 and DDR2 small molecule inhibitors covering their design approaches, structure-activity relationship (SAR), biological activity, and selectivity.


Assuntos
Receptor com Domínio Discoidina 1/antagonistas & inibidores , Receptor com Domínio Discoidina 2/antagonistas & inibidores , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Animais , Sítios de Ligação , Biomarcadores Tumorais , Receptor com Domínio Discoidina 1/química , Receptor com Domínio Discoidina 1/metabolismo , Receptor com Domínio Discoidina 2/química , Receptor com Domínio Discoidina 2/metabolismo , Gerenciamento Clínico , Suscetibilidade a Doenças , Desenho de Fármacos , Humanos , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/patologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Ligação Proteica , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Relação Estrutura-Atividade
19.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208561

RESUMO

It has been proposed that a "common core" of pathologic pathways exists for the large family of amyloid-associated neurodegenerations, including Alzheimer's, Parkinson's, type II diabetes and Creutzfeldt-Jacob's Disease. Aggregates of the involved proteins, independently from their primary sequence, induced neuron membrane permeabilization able to trigger an abnormal Ca2+ influx leading to synaptotoxicity, resulting in reduced expression of synaptic proteins and impaired synaptic transmission. Emerging evidence is now focusing on low-molecular-weight prefibrillar oligomers (PFOs), which mimic bacterial pore-forming toxins that form well-ordered oligomeric membrane-spanning pores. At the same time, the neuron membrane composition and its chemical microenvironment seem to play a pivotal role. In fact, the brain of AD patients contains increased fractions of anionic lipids able to favor cationic influx. However, up to now the existence of a specific "common structure" of the toxic aggregate, and a "common mechanism" by which it induces neuronal damage, synaptotoxicity and impaired synaptic transmission, is still an open hypothesis. In this review, we gathered information concerning this hypothesis, focusing on the proteins linked to several amyloid diseases. We noted commonalities in their structure and membrane activity, and their ability to induce Ca2+ influx, neurotoxicity, synaptotoxicity and impaired synaptic transmission.


Assuntos
Amiloide/química , Amiloide/metabolismo , Proteínas Amiloidogênicas/química , Proteínas Amiloidogênicas/metabolismo , Multimerização Proteica , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Suscetibilidade a Doenças , Humanos , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Relação Estrutura-Atividade
20.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207557

RESUMO

Nucleotide excision repair (NER) is the most versatile DNA repair pathway, which can remove diverse bulky DNA lesions destabilizing a DNA duplex. NER defects cause several autosomal recessive genetic disorders. Xeroderma pigmentosum (XP) is one of the NER-associated syndromes characterized by low efficiency of the removal of bulky DNA adducts generated by ultraviolet radiation. XP patients have extremely high ultraviolet-light sensitivity of sun-exposed tissues, often resulting in multiple skin and eye cancers. Some XP patients develop characteristic neurodegeneration that is believed to derive from their inability to repair neuronal DNA damaged by endogenous metabolites. A specific class of oxidatively induced DNA lesions, 8,5'-cyclopurine-2'-deoxynucleosides, is considered endogenous DNA lesions mainly responsible for neurological problems in XP. Growing evidence suggests that XP is accompanied by defective mitophagy, as in primary mitochondrial disorders. Moreover, NER pathway is absent in mitochondria, implying that the mitochondrial dysfunction is secondary to nuclear NER defects. In this review, we discuss the current understanding of the NER molecular mechanism and focuses on the NER linkage with the neurological degeneration in patients with XP. We also present recent research advances regarding NER involvement in oxidative DNA lesion repair. Finally, we highlight how mitochondrial dysfunction may be associated with XP.


Assuntos
Reparo do DNA , Doenças Neurodegenerativas , Raios Ultravioleta/efeitos adversos , Xeroderma Pigmentoso , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/terapia , Xeroderma Pigmentoso/genética , Xeroderma Pigmentoso/metabolismo , Xeroderma Pigmentoso/patologia
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