Deficient Chaperone-Mediated Autophagy in Liver Leads to Metabolic Dysregulation (original) (raw)

“…In this regard, we have examined the role of CMA. Our data do not suggest an accumulation of CMA substrates, 40 as would be expected with ablation of the LAMP2A isoform in lamp2 null mice), 28 which could conceivably be due to upregulation of alternate protein degradation mechanisms. Importantly, the levels of these substrates were not altered by the intermittent fasting regimen, suggesting that CMA is unlikely to be a significant contributor to the observed cardioprotective effects.…”

Section: Discussioncontrasting

“…40 This pathway has been shown to be activated in the myocardium by fasting, in vivo, and by oxidative stress. 41 To examine its role in intermittent-fasting induced cardioprotection, we assessed the abundance of candidate proteins that are known chaperonemediated autophagy substrates 40 in the myocardium, in these models. Interestingly, our data do not demonstrate any significant alteration in abundance of these proteins with intermittent fasting or Lamp2 ablation (which also results in loss of the LAMP2A isoform; 28 see Fig.…”

Section: Intermittent Fasting Modulates Oxidative Stress In the Myocamentioning

“…This lysosomal degradation occurred, in large part, through CMA, as genetic blockage of this pathway almost completely abolished lysosomal degradation of WT tau and led to its accumulation (Fig. 1a,b; GAPDH is shown as an example of a well‐characterized CMA substrate (Aniento et al ., 1993) known to accumulate intracellularly upon blockage of CMA (Schneider et al ., 2014)). Tau‐A152T displayed very similar degradation dynamics, although this mutation slightly reduced tau's rates of lysosomal degradation (20% inhibition) when compared with WT tau (Fig.…”

Section: Resultsmentioning

“…Blockage of CMA in vitro and in vivo is compensated for by upregulation of macroautophagy and of the proteasome system in most cell types (17,18). Conversely, cells respond to inhibition of macroautophagy or the proteasome by constitutively activating CMA (19)(20)(21)(22).…”

Section: Chaperone-mediated Autophagy (Cma) 21 General Descriptionmentioning