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. 2020 Dec 14;141(2):217–233. doi: 10.1007/s00401-020-02249-0

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© The Author(s) 2020

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 5 — Association of ubiquitin and proteasome system function with pTau pathology and AoO in PSEN1 E280A FAD. a Schematic representation for AoO significantly associated variants in PSEN1 E280A FAD cases, early and average AoO FAD (E-AOFAD, n = 6), and LOFAD (n = 8), as characterized by whole-exome capture. Yellow = identified uncommon variants were present in both alleles, Gree n = identified uncommon variants were present in only one allele and, Blue = identified common variants were present in both alleles. b Protein network analysis of main AD-related genes and genes showing association with AoO in evaluated PSEN1 E280A FAD cases. Black ovals depict AD-related genes, pink circles early AoO-associated genes, and green circles late AoO-associated genes. Genes directly involved in the ubiquitin–proteasome system are underscored and connected with dotted lines. c Chord diagram of statistically significant biological pathways (GO:BP analysis) in which AoO-associated genes take part. Four pathways, underscored, are related with protein metabolism and catabolism. d Representative semi-denaturing immunoblot for polyubiquitinated proteins (PolyUb) in TBS-soluble fractions from temporal cortex of early and average AoO FAD. E. Densitometric analysis of PolyUb in TBS-soluble fractions from temporal cortex of E-AOFAD (n = 5) and LOFAD (n = 7). E-AOFAD cases showed significantly higher levels of PolyUb. F. Chymotrypsin S20 proteasome activity in temporal cortex tissue from controls (n = 4), E-AOFAD (n = 6), and LOFAD (n = 8) cases as detected by LLVY-AMC substrate. LOFAD cases showed significantly higher Chymotrypsine proteasome activity when compared to E-AOFAD cases. g Densitometric analysis of co-immunoprecipitation using monoclonal polyubiquitin antibody as bait and immunoblots for total Tau, pTau-S400, and pTau-S422 in TBS-soluble fractions from temporal cortex of E-AOFAD (n = 5) and LOFAD (n = 7). There were no significant differences between E-AOFAD and LOFAD cases for pTau-S400/total Tau ratio. However, E-AOFAD cases showed higher pTau-S422/total Tau ratio than LOFAD cases. h Bar graph representing pTau seeding capacity assays in temporal cortices homogenates from negative Controls (n = 2), SAD (n = 2), E-AOFAD (n = 5), and LOFAD (n = 5) cases. Both FAD groups showed increased pTau seeding activity when compared to negative controls. (* = p ≤ 0.05)