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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Autophagosomes cooperate in the degradation of intracellular C-terminal fragments of the amyloid precursor protein via the MVB/lysosomal pathway

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Gonzalez, Alexis E. ; Munoz, Vanessa C. ; Cavieres, Viviana A. ; Bustamante, Hianara A. ; Cornejo, Victor-Hugo ; Januario, Yunan C. ; Gonzalez, Ibeth ; Hetz, Claudio ; daSilva, Luis L. ; Rojas-Fernandez, Alejandro ; Hay, Ronald T. ; Mardones, Gonzalo A. ; Burgos, Patricia V.
Número total de Autores: 13
Tipo de documento: Artigo Científico
Fonte: FASEB JOURNAL; v. 31, n. 6, p. 2446-2459, JUN 2017.
Citações Web of Science: 12
Resumo

Brain regions affected by Alzheimer disease (AD) displaywell-recognized early neuropathologic features in the endolysosomal and autophagy systems of neurons, including enlargement of endosomal compartments, progressive accumulation of autophagic vacuoles, and lysosomal dysfunction. Although the primary causes of these disturbances are still under investigation, a growing body of evidence suggests that the amyloid precursor protein (APP) intracellular C-terminal fragment beta (C99), generated by cleavage of APP by beta-site APP cleaving enzyme 1 (BACE-1), is the primary cause of the endosome enlargement inADand the earliest initiator of synaptic plasticity and long-termmemory impairment. The aim of the present study was to evaluate the possible relationship between the endolysosomal degradation pathway and autophagy on the proteolytic processing and turnover of C99. We found that pharmacologic treatments that either inhibit autophagosome formation or block the fusion of autophagosomes to endolysosomal compartments caused an increase in C99 levels. We also found that inhibition of autophagosome formation by depletion of Atg5 led to higher levels of C99 and to its massive accumulation in the lumen of enlarged perinuclear, lysosomal-associated membrane protein 1 (LAMP1)-positive organelles. In contrast, activation of autophagosome formation, either by starvation or by inhibition of the mammalian target of rapamycin, enhanced lysosomal clearance of C99. Altogether, our results indicate that autophagosomes are key organelles to help avoid C99 accumulation preventing its deleterious effects. (AU)

Processo FAPESP: 14/25812-0 - Estudo sobre as interações moleculares de HIV-1 com o sistema de endomembranas da célula hospedeira
Beneficiário:Luis Lamberti Pinto da Silva
Linha de fomento: Auxílio à Pesquisa - Regular