Age-related macular degeneration (AMD) is the most common reason of visual impairment in the elderly in the Western countries. The degeneration of retinal pigment epithelial cells (RPE) causes secondarily adverse effects on neural retina leading to visual loss. The aging characteristics of the RPE involve lysosomal accumulation of lipofuscin and extracellular protein aggregates called "drusen". Molecular mechanisms behind protein aggregations are weakly understood. There is intriguing evidence suggesting that protein SQSTM1/p62, together with autophagy, has a role in the pathology of different degenerative diseases. It appears that SQSTM1/p62 is a connecting link between autophagy and proteasome mediated proteolysis, and expressed strongly under the exposure to various oxidative stimuli and proteasomal inhibition. ELAVL1/HuR protein is a post-transcriptional factor, which acts mainly as a positive regulator of gene expression by binding to specific mRNAs whose corresponding proteins are fundamental for key cellular functions. We here show that, under proteasomal inhibitor MG-132, ELAVL1/HuR is up-regulated at both mRNA and protein levels, and that this protein binds and post-transcriptionally regulates SQSTM1/p62 mRNA in ARPE-19 cell line. Furthermore, we observed that proteasomal inhibition caused accumulation of SQSTM1/p62 bound irreversibly to perinuclear protein aggregates. The addition of the AMPK activator AICAR was pro-survival and promoted cleansing by autophagy of the former complex, but not of the ELAVL1/HuR accumulation, indeed suggesting that SQSTM1/p62 is decreased through autophagy-mediated degradation, while ELAVL1/HuR through the proteasomal pathway. Interestingly, when compared to human controls, AMD donor samples show strong SQSTM1/p62 rather than ELAVL1/HuR accumulation in the drusen rich macular area suggesting impaired autophagy in the pathology of AMD.
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|Titolo:||Autophagy Activation Clears ELAVL1/HuR-Mediated Accumulation of SQSTM1/p62 during Proteasomal Inhibition in Human Retinal Pigment Epithelial Cells|
|Autori:||J., Viiri; M., Amadio; N., Marchesi; J. M. T., Hyttinen; N., Kivinen; R., Sironen; K., Rilla; S., Akhtar; Provenzani, Alessandro; D'Agostino, Vito Giuseppe; S., Govoni; A., Pascale; H., Agostini; G., Petrovski; A., Salminen; K., Kaarniranta|
|Titolo del periodico:||PLOS ONE|
|Anno di pubblicazione:||2013|
|Codice identificativo Scopus:||2-s2.0-84880843826|
|Codice identificativo Pubmed:||23922739|
|Codice identificativo ISI:||WOS:000323369700043|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1371/journal.pone.0069563|
|Appare nelle tipologie:||03.1 Articolo su rivista (Journal article)|