Interplay of pathogenic forms of human tau with different autophagic pathways

Abstract

SummaryLoss of neuronal proteostasis, a common feature of the aging brain, is accelerated in neurodegenerative disorders, including different types of tauopathies. Aberrant turnover of tau, a microtubule‐stabilizing protein, contributes to its accumulation and subsequent toxicity in tauopathy patients’ brains. A direct toxic effect of pathogenic forms of tau on the proteolytic systems that normally contribute to their turnover has been proposed. In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone‐mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this age‐related disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk‐associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway. We also found defective autophagic degradation of tau when using mutations that mimic common posttranslational modifications in tau or known to promote its aggregation. Interestingly, although most mutations markedly reduced degradation of tau through autophagy, the step of this process preferentially affected varies depending on the type of tau mutation. Overall, our studies unveil a complex interplay between the multiple modifications of tau and selective forms of autophagy that may determine its physiological degradation and its faulty clearance in the disease context.

Tau protein aggregation is associated with cellular senescence in the brain

“…Furthermore, SA β‐gal‐reactive cells were observed even in very young mice (1 month old) and the number of SA β‐gal‐reactive cells was positively correlated with brain mass ( R 2 = 0.4852, p  = 0.0039 Supporting Information Figure S3). While our results indicate that SA β‐gal reactivity did not correlate with other senescence markers or brain atrophy, the observed increase in Glb1 gene expression along with a decrease in lysosomal activity at pH 6.0, compared to controls, is suggestive of tau‐associated lysosomal defects, which have been reported by others (Caballero et al, 2018; Wang, Martinez‐Vicente, et al, 2009). …”

Chaperone-mediated autophagy and endosomal microautophagy: Jointed by a chaperone

“…In fact, studies in other cell types and organs such (i.e. liver, brain) confirmed that non-immunological cells also display this form of autophagy (8,90) that has been named eMI to highlight its cellular localization.…”

“…In fact, an early proposed reporter for CMA activity based on fluorescent tagging of GAPDH has now been shown to undergo degradation by both pathways, thus limiting its usability to differentiate between them (91). Endogenous proteins such as Tau, a cytoskeletal protein associated with neurodegeneration, also undergo simultaneous degradation by both eMI and CMA (90). The fact that pathogenic mutations in tau switch the percentage of the protein degraded by each of these pathways (90), suggests that intrinsic properties of the protein (i.e.…”

“…Endogenous proteins such as Tau, a cytoskeletal protein associated with neurodegeneration, also undergo simultaneous degradation by both eMI and CMA (90). The fact that pathogenic mutations in tau switch the percentage of the protein degraded by each of these pathways (90), suggests that intrinsic properties of the protein (i.e. mutations, posttranslational modifications, oligomeric state, etc.)…”

“…GAPDH) are internalized in LE but their degradation is markedly less efficient than in lysosomes (8,90). It is possible that in these cases most of the degradation occurs by endosomal/lysosomal fusion.…”