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1.
Front Neurol ; 14: 1239653, 2023.
Article de Anglais | MEDLINE | ID: mdl-37638180

RÉSUMÉ

Tau is a protein that has received national mainstream recognition for its potential negative impact to the brain. This review succinctly provides information on the structure of tau and its normal physiological functions, including in hibernation and changes throughout the estrus cycle. There are many pathways involved in phosphorylating tau including diabetes, stroke, Alzheimer's disease (AD), brain injury, aging, and drug use. The common mechanisms for these processes are put into context with changes observed in mild and repetitive mild traumatic brain injury (TBI). The phosphorylation of tau is a part of the progression to pathology, but the ability for tau to aggregate and propagate is also addressed. Summarizing both the functional and dysfunctional roles of tau can help advance our understanding of this complex protein, improve our care for individuals with a history of TBI, and lead to development of therapeutic interventions to prevent or reverse tau-mediated neurodegeneration.

2.
BMJ Case Rep ; 13(12)2020 Dec 09.
Article de Anglais | MEDLINE | ID: mdl-33298483

RÉSUMÉ

A 49-year-old man with a recent history of atrial tachycardia and intracardiac thrombus presented to the emergency department with melena and cardiac tamponade. Physical examination was notable for a vascular mass at the right lower gingival sulcus and a right chest wall nodule. Enteroscopy revealed a target lesion with friable ulcer in the gastric body. Cardiac MRI revealed a large right atrial mass, previously thought to represent thrombus. The patient was ultimately diagnosed with primary cardiac angiosarcoma (PCAS) by histopathology of gingival, gastric and subcutaneous lesions. This case illustrates the significant morbidity and mortality resulting from aggressive local invasion and growth of PCAS, as well as the challenge of differentiating between primary thrombosis and vascular malignancy. Misdiagnosis of this elusive clinical entity may be costly, potentially resulting in delay of intervention and adverse effects of alternate therapies such as anticoagulation.


Sujet(s)
Tumeurs du coeur/diagnostic , Hémangiosarcome/diagnostic , Tamponnade cardiaque/étiologie , Diagnostic différentiel , Issue fatale , Atrium du coeur/anatomopathologie , Tumeurs du coeur/anatomopathologie , Tumeurs du coeur/physiopathologie , Hémangiosarcome/anatomopathologie , Hémangiosarcome/physiopathologie , Humains , Mâle , Méléna/étiologie , Adulte d'âge moyen , Épanchement péricardique/étiologie , Thrombose veineuse
3.
Acta Neuropathol ; 134(4): 629-653, 2017 Oct.
Article de Anglais | MEDLINE | ID: mdl-28527044

RÉSUMÉ

Numerous pathological amyloid proteins spread from cell to cell during neurodegenerative disease, facilitating the propagation of cellular pathology and disease progression. Understanding the mechanism by which disease-associated amyloid protein assemblies enter target cells and induce cellular dysfunction is, therefore, key to understanding the progressive nature of such neurodegenerative diseases. In this study, we utilized an imaging-based assay to monitor the ability of disease-associated amyloid assemblies to rupture intracellular vesicles following endocytosis. We observe that the ability to induce vesicle rupture is a common feature of α-synuclein (α-syn) assemblies, as assemblies derived from WT or familial disease-associated mutant α-syn all exhibited the ability to induce vesicle rupture. Similarly, different conformational strains of WT α-syn assemblies, but not monomeric or oligomeric forms, efficiently induced vesicle rupture following endocytosis. The ability to induce vesicle rupture was not specific to α-syn, as amyloid assemblies of tau and huntingtin Exon1 with pathologic polyglutamine repeats also exhibited the ability to induce vesicle rupture. We also observe that vesicles ruptured by α-syn are positive for the autophagic marker LC3 and can accumulate and fuse into large, intracellular structures resembling Lewy bodies in vitro. Finally, we show that the same markers of vesicle rupture surround Lewy bodies in brain sections from PD patients. These data underscore the importance of this conserved endocytic vesicle rupture event as a damaging mechanism of cellular invasion by amyloid assemblies of multiple neurodegenerative disease-associated proteins, and suggest that proteinaceous inclusions such as Lewy bodies form as a consequence of continued fusion of autophagic vesicles in cells unable to degrade ruptured vesicles and their amyloid contents.


Sujet(s)
Protéines amyloïdogènes/métabolisme , Transport biologique/physiologie , Vésicules de transport/métabolisme , Animaux , Autophagie , Encéphale/métabolisme , Encéphale/anatomopathologie , Cellules cultivées , Femelle , Fluorescéines , Humains , Corps de Lewy/métabolisme , Corps de Lewy/anatomopathologie , Mâle , Neurones/métabolisme , Neurones/ultrastructure , Maladie de Parkinson/métabolisme , Maladie de Parkinson/anatomopathologie , Phosphatidylglycérol , Rats , Vésicules de transport/ultrastructure , Liposomes unilamellaires , alpha-Synucléine/métabolisme
4.
J Biol Chem ; 291(9): 4374-85, 2016 Feb 26.
Article de Anglais | MEDLINE | ID: mdl-26719332

RÉSUMÉ

Although trace levels of phosphorylated α-synuclein (α-syn) are detectable in normal brains, nearly all α-syn accumulated within Lewy bodies in Parkinson disease brains is phosphorylated on serine 129 (Ser-129). The role of the phosphoserine residue and its effects on α-syn structure, function, and intracellular accumulation are poorly understood. Here, co-expression of α-syn and polo-like kinase 2 (PLK2), a kinase that targets Ser-129, was used to generate phosphorylated α-syn for biophysical and biological characterization. Misfolding and fibril formation of phosphorylated α-syn isoforms were detected earlier, although the fibrils remained phosphatase- and protease-sensitive. Membrane binding of α-syn monomers was differentially affected by phosphorylation depending on the Parkinson disease-linked mutation. WT α-syn binding to presynaptic membranes was not affected by phosphorylation, whereas A30P α-syn binding was greatly increased, and A53T α-syn was slightly lower, implicating distal effects of the carboxyl- on amino-terminal membrane binding. Endocytic vesicle-mediated internalization of pre-formed fibrils into non-neuronal cells and dopaminergic neurons matched the efficacy of α-syn membrane binding. Finally, the disruption of internalized vesicle membranes was enhanced by the phosphorylated α-syn isoforms, a potential means for misfolded extracellular or lumenal α-syn to access cytosolic α-syn. Our results suggest that the threshold for vesicle permeabilization is evident even at low levels of α-syn internalization and are relevant to therapeutic strategies to reduce intercellular propagation of α-syn misfolding.


Sujet(s)
Endocytose , Maladie de Parkinson/génétique , Agrégation pathologique de protéines/métabolisme , Maturation post-traductionnelle des protéines , Protein-Serine-Threonine Kinases/métabolisme , Synaptosomes/métabolisme , alpha-Synucléine/métabolisme , Substitution d'acide aminé , Animaux , Animaux nouveau-nés , Lignée cellulaire , Cellules cultivées , Neurones dopaminergiques/cytologie , Neurones dopaminergiques/métabolisme , Neurones dopaminergiques/anatomopathologie , Humains , Mésencéphale/cytologie , Mésencéphale/métabolisme , Mésencéphale/anatomopathologie , Souris , Mutation , Maladie de Parkinson/métabolisme , Maladie de Parkinson/anatomopathologie , Phosphorylation , Agrégation pathologique de protéines/génétique , Agrégation pathologique de protéines/anatomopathologie , Pliage des protéines , Protein-Serine-Threonine Kinases/génétique , Protéines de fusion recombinantes/génétique , Protéines de fusion recombinantes/métabolisme , Protéines recombinantes/composition chimique , Protéines recombinantes/génétique , Protéines recombinantes/métabolisme , Sérine/métabolisme , Synaptosomes/anatomopathologie , alpha-Synucléine/composition chimique , alpha-Synucléine/génétique
5.
Bioorg Med Chem Lett ; 20(18): 5389-93, 2010 Sep 15.
Article de Anglais | MEDLINE | ID: mdl-20719505

RÉSUMÉ

Apoptosis is a highly regulated process by which excessive cells are eliminated in order to maintain normal cell development and tissue homeostasis. Resistance to apoptosis often contributes to failure in cancer prevention and treatment. Apoptotic cell death regulators are considered important targets for discovery and development of new therapeutic agents in oncology research. A class of novel aza-lupane triterpenoids were designed, synthesized, and evaluated for antitumor activity against a panel of cancer cell lines of different histogenic origin and for ability to induce apoptosis. 3,30-Bis(aza) derivatives were identified not only to possess improved cytotoxicity compared to the natural product betulinic acid but also to affect cell death predominantly via apoptosis, whereas the mono(aza) derivatives apparently triggered cell death via different, non-apoptotic pathway(s).


Sujet(s)
Antinéoplasiques/composition chimique , Antinéoplasiques/pharmacologie , Apoptose/effets des médicaments et des substances chimiques , Triterpènes/composition chimique , Triterpènes/pharmacologie , Antinéoplasiques/synthèse chimique , Lignée cellulaire tumorale , Cytotoxines/synthèse chimique , Cytotoxines/composition chimique , Cytotoxines/pharmacologie , Tests de criblage d'agents antitumoraux , Humains , Tumeurs/traitement médicamenteux , Triterpènes pentacycliques , Relation structure-activité , Triterpènes/synthèse chimique , Acide bétulinique
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