p(HGNC:NPEPPS)
Aminopeptidases are a group of enzymes that cleave from the N-terminal end of a protein. The family includes alanyl, arginyl, and glutamyl peptidases. Puromycin sensitive aminopeptidase (PSA) is an alanyl peptidase that is responsible for s90% of the aminopeptidase activity in the brain(10). PubMed:24027553
PSA has been shown to be involved in the induction of autophagy and specifically the formation of autophagosomes, in a model of overexpressed mutant huntingtin (32). Thus, the in vivo effects of PSA on promoting tau clearance may relate to its ability to modulate the key clearance pathway for abnormal and aggregated proteins (to be described in more detail below). PubMed:24027553
Interestingly, PSA was found to be elevated in the cerebellum of these TAUP301L mice (10). The levels of PSA are also higher in human cerebellum compared to cortex in both controls and FTD cases. A slight elevation in PSA was also observed in FTD cortices compared to controls. PubMed:24027553
Interestingly, PSA was found to be elevated in the cerebellum of these TAUP301L mice (10). The levels of PSA are also higher in human cerebellum compared to cortex in both controls and FTD cases. A slight elevation in PSA was also observed in FTD cortices compared to controls. PubMed:24027553
Aminopeptidases are a group of enzymes that cleave from the N-terminal end of a protein. The family includes alanyl, arginyl, and glutamyl peptidases. Puromycin sensitive aminopeptidase (PSA) is an alanyl peptidase that is responsible for s90% of the aminopeptidase activity in the brain(10). PubMed:24027553
Interestingly, PSA was found to be elevated in the cerebellum of these TAUP301L mice (10). The levels of PSA are also higher in human cerebellum compared to cortex in both controls and FTD cases. A slight elevation in PSA was also observed in FTD cortices compared to controls. PubMed:24027553
In addition, a non-functional PSA mutant exacerbated tau pathology in a Drosophila model of tauopathy, while overexpressing PSA ameliorated the tau phenotype and diminished tau levels (10). Overexpressing PSA had a similar effect in the TAUP301L mice, reducing the pathologic phenotype (delaying paralysis, increasing motor neuron density in the spinal cord, decreasing gliosis) and decreasing tau levels (12). PubMed:24027553
Interestingly, PSA was found to be elevated in the cerebellum of these TAUP301L mice (10). The levels of PSA are also higher in human cerebellum compared to cortex in both controls and FTD cases. A slight elevation in PSA was also observed in FTD cortices compared to controls. PubMed:24027553
In addition, a non-functional PSA mutant exacerbated tau pathology in a Drosophila model of tauopathy, while overexpressing PSA ameliorated the tau phenotype and diminished tau levels (10). Overexpressing PSA had a similar effect in the TAUP301L mice, reducing the pathologic phenotype (delaying paralysis, increasing motor neuron density in the spinal cord, decreasing gliosis) and decreasing tau levels (12). PubMed:24027553
In addition, a non-functional PSA mutant exacerbated tau pathology in a Drosophila model of tauopathy, while overexpressing PSA ameliorated the tau phenotype and diminished tau levels (10). Overexpressing PSA had a similar effect in the TAUP301L mice, reducing the pathologic phenotype (delaying paralysis, increasing motor neuron density in the spinal cord, decreasing gliosis) and decreasing tau levels (12). PubMed:24027553
For example, it has been shown that the isomerase Pin1, which has been implicated in AD (30), had opposite effects on P301L and wild-type tau degradation (31). An alternative explanation for the effects of PSA may be that PSA is indirectly regulating tau degradation. PubMed:24027553
In addition, a non-functional PSA mutant exacerbated tau pathology in a Drosophila model of tauopathy, while overexpressing PSA ameliorated the tau phenotype and diminished tau levels (10). Overexpressing PSA had a similar effect in the TAUP301L mice, reducing the pathologic phenotype (delaying paralysis, increasing motor neuron density in the spinal cord, decreasing gliosis) and decreasing tau levels (12). PubMed:24027553
In addition, a non-functional PSA mutant exacerbated tau pathology in a Drosophila model of tauopathy, while overexpressing PSA ameliorated the tau phenotype and diminished tau levels (10). Overexpressing PSA had a similar effect in the TAUP301L mice, reducing the pathologic phenotype (delaying paralysis, increasing motor neuron density in the spinal cord, decreasing gliosis) and decreasing tau levels (12). PubMed:24027553
PSA was able to cleave recombinant tau in vitro, as well as tau from control human brain (11). However, the data presented in this study suggest that PSA is cleaving tau from both the C- and N-terminal ends, which is not expected from an aminopeptidase. Additionally, other studies failed to demonstrate tau cleavage by PSA (28, 29). PubMed:24027553
PSA was able to cleave recombinant tau in vitro, as well as tau from control human brain (11). However, the data presented in this study suggest that PSA is cleaving tau from both the C- and N-terminal ends, which is not expected from an aminopeptidase. Additionally, other studies failed to demonstrate tau cleavage by PSA (28, 29). PubMed:24027553
PSA has been shown to be involved in the induction of autophagy and specifically the formation of autophagosomes, in a model of overexpressed mutant huntingtin (32). Thus, the in vivo effects of PSA on promoting tau clearance may relate to its ability to modulate the key clearance pathway for abnormal and aggregated proteins (to be described in more detail below). PubMed:24027553
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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.