INVESTIGADORES
BOLLO Mariana Ines
congresos y reuniones científicas
Título:
GM2-ganglioside accumulation mediates Endoplasmic Reticulum calcium depletion and PERK signaling activation
Autor/es:
VIRGOLINI, M.J. LOPEZ, PHH AND BOLLO M.
Lugar:
Puerto Varas
Reunión:
Congreso; XXVIII Reunión Anual de la Sociedad de Biologia Celular de Chile; 2014
Resumen:
<!-- /* Font Definitions */@font-face{font-family:"ＭＳ 明朝";mso-font-charset:78;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:-536870145 1791491579 18 0 131231 0;}@font-face{font-family:"ＭＳ 明朝";mso-font-charset:78;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:-536870145 1791491579 18 0 131231 0;}@font-face{font-family:Calibri;panose-1:2 15 5 2 2 2 4 3 2 4;mso-font-charset:0;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:-520092929 1073786111 9 0 415 0;} /* Style Definitions */p.MsoNormal, li.MsoNormal, div.MsoNormal{mso-style-unhide:no;mso-style-qformat:yes;mso-style-parent:"";margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;line-height:115%;mso-pagination:widow-orphan;font-size:11.0pt;font-family:Calibri;mso-fareast-font-family:Calibri;mso-bidi-font-family:"Times New Roman";mso-ansi-language:ES-AR;}.MsoChpDefault{mso-style-type:export-only;mso-default-props:yes;font-size:10.0pt;mso-ansi-font-size:10.0pt;mso-bidi-font-size:10.0pt;font-family:Calibri;mso-ascii-font-family:Calibri;mso-fareast-font-family:Calibri;mso-hansi-font-family:Calibri;}@page WordSection1{size:8.5in 11.0in;margin:70.85pt 85.05pt 70.85pt 85.05pt;mso-header-margin:35.4pt;mso-footer-margin:35.4pt;mso-paper-source:0;}div.WordSection1{page:WordSection1;}-->Introduction:The accumulation of misfolded proteins within the endoplasmic reticulum (ER)triggers a cellular process known as the Unfolded Protein Response (UPR), inwhich the cell attempts to restore ER homeostasis. IfER damage is persistent or excessive, an apoptotic response is initiated. Itis well accepted that ER calcium depletion induces ER stress. PERK is an early ER stress sensor that attenuatesprotein synthesis. We demonstrated thatCalcineurin (CN) associates with PERK, enhancinginhibition of protein translation and cell viability. But PERKsignaling, including pro-apoptotic transcriptionfactor CHOP, persists activatedunder prolonged stress. Chronic UPR is proposed to contribute to the pathology of manyneurodegenerative diseases. GM2-gangliosidosis arecharacterized by a progressive neurodegeneration due to deficiency in b-hexosaminidase activity. However, the mechanisms that determine how GM2accumulation triggers neuronal cell death remain unknown.Material and Methods: N2Acells were either loaded with GM2 or treated with ShRNA specific for b-hexosaminidase. The GM2 accumulation in the ER was assessed by thinlayer chromatography and immunocytochemistry. Besides, we exanimated whetherUPR was activated using immunopresipitations, western-bloting and Ca2+measurements.Results and Discussion: We report that theGM2 accumulation in the ER induces PERK activation, and provokes up-regulationof either CN or CHOP, at different time points. This stress also decreases theER calcium content. Moreover, calcium depletion, as well as CHOP levelincrease, was enhanced by MBCD, a pharmacological agent that augmentganglioside delivery to the ER. This finding suggests that varied time courseof the individual PERK signaling elements influence the cell?s ultimate fate inresponse to abnormal GM2 accumulation.
