What is it about?
Our study addresses the fact that despite significant progress in the understanding of Alzheimer's disease (AD) further research is needed to elucidate the cellular and molecular mechanisms underlying its pathogenesis. Although increased amyloidogenic proteolytic processing of the amyloid precursor protein is considered an important factor in AD pathogenesis, several lines of evidence indicate that defects in the endo-lysosomal and autophagy pathways of protein degradation are also critical. In our study, we describe that inhibition of either autophagosome formation or the fusion of autophagosomes to lysosomes caused a dramatic increase in the levels of C-terminal fragments (CTFs), including C99, the immediate precursor of pathogenic Aβ-peptide. Of note, we found that CTFs accumulated in structures reminiscent of intra-luminal vesicles (ILVs) of multivesicuclar bodies (MVBs), suggesting that autophagy-flux is necessary for the lysosomal clearance of CTFs. We also show that the activation of autophagosome formation enhanced the lysosomal clearance of C99. Therefore, we propose that autophagosomes are key organelles that connect with the MVB/lysosomal pathway for the efficient turnover of CTFs.
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Why is it important?
Our data allow us to propose that autophagosomes have an important function in amyloid precursor protein (APP) and its carboxy terminal fragments (CTFs) proteostasis. Our proposal is consistent with the observation that autophagosomes gradually accumulate in dystrophic neurites; a well-documented neuropathological hallmark of AD.
Perspectives
The model of this study predicts that conditions that compromise the fusion of autophagosomes to endo-lysosomal organelles accumulate C99, and thus promote neuronal dysfunction. Furthermore, other lysosomal substrates can accumulate within endosomes when autophagy is impaired. For example failures in autophagy could impact the balance of proteins that are incorporated into multivesicular bodies. Hence, the pharmacological booster of autophagy could promote the degradation potentially toxic macromolecules destined to the endo-lysosomal pathway, emerging as an attractive approach for therapeutic intervention neurodegenerative disorders.
Alexis Gonzalez
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This page is a summary of:
Autophagosomes cooperate in the degradation of intracellular C-terminal fragments of the amyloid precursor protein
via
the MVB/lysosomal pathway
, The FASEB Journal, March 2017, Federation of American Societies For Experimental Biology (FASEB),
DOI: 10.1096/fj.201600713r.
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