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1.
Biochim Biophys Acta Biomembr ; 1866(5): 184331, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38718958

RESUMO

The causative genes for neurodegenerative polyglutamine (polyQ) diseases produce homopolymeric polyglutamine (polyQ), polyserine (polyS), polyalanine (polyA), polycysteine (polyC), and polyleucine (polyL) sequences by repeat-associated non-AUG (RAN) translation. The cytotoxicity of the intracellular polyQ and RAN products has been extensively investigated. However, little is known about the toxicity of the extracellular polyQ and RAN products on the membranes of viable cells. Because polyQ aggregates induce a deflated morphology of a model membrane, we hypothesized that extracellular polyQ and RAN products might affect the membrane properties of viable cells. In this study, we demonstrated that exogenous polyS fibrils but not polyS or polyQ non-fibril aggregates altered the thermal phase transition behavior of a model membrane composed of a phosphatidylcholine bilayer using differential scanning calorimetry. PolyS fibrils induced morphological changes in viable red blood cells (RBCs). However, both polyS and polyQ non-fibril aggregates had no effects on RBCs. These results highlight the possibility that extracellular fibrils generated from RAN products may alter the properties of neuronal cell membranes, which may contribute to changes in the brain pathology.


Assuntos
Eritrócitos , Lipossomos , Peptídeos , Fosfatidilcolinas , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Fosfatidilcolinas/química , Humanos , Lipossomos/química , Peptídeos/química , Peptídeos/farmacologia , Membrana Celular/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/química , Transição de Fase , Bicamadas Lipídicas/química , Bicamadas Lipídicas/metabolismo
2.
Sci Rep ; 11(1): 23441, 2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34873226

RESUMO

In polyalanine (PA) diseases, the disease-causing transcription factors contain an expansion of alanine repeats. While aggregated proteins that are responsible for the pathogenesis of neurodegenerative disorders show cell-to-cell propagation and thereby exert toxic effects on the recipient cells, whether this is also the case with expanded PA has not been studied. It is also not known whether the internalized PA is toxic to recipient cells based on the degree of aggregation. In this study, we therefore prepared different degrees of aggregation of a peptide having 13 alanine repeats without flanking sequences of PA disease-causative proteins (13A). The aggregated 13A was spontaneously taken up by neuron-like cultured cells. Functionally, strong aggregates but not weak aggregates displayed a deficit in neuron-like differentiation in vitro. Moreover, the injection of strong but not weak 13A aggregates into the ventricle of mice during the neonatal stage led to enhanced spontaneous motor activity later in life. Thus, PA in the extracellular space has the potential to enter adjacent cells, and may exert toxicity depending on the degree of aggregation.


Assuntos
Alanina/química , Encéfalo/efeitos dos fármacos , Peptídeos/química , Animais , Comportamento Animal , Espaço Extracelular , Camundongos , Camundongos Endogâmicos ICR , Microscopia Eletrônica de Transmissão , Destreza Motora , Neurociências , Células PC12 , Estrutura Secundária de Proteína , Ratos , Fatores de Transcrição/metabolismo , Transcrição Gênica , Ativação Transcricional , Expansão das Repetições de Trinucleotídeos
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