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Protein homeostasis (proteostasis) is at the core of cellular functions. The European network PROTEOSTASIS was created to steer research and foster collaborations in the interconnected fields of posttranslational modifications by ubiquitin family members and protein turnover by proteasome, autophagy, and lysosomal systems in health and diseases, across the kingdoms of life., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The BrainNet Europe consortium assessed the reproducibility in the assignment of the type of frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP) 43 following current recommendations. The agreement rates were influenced by the immunohistochemical (IHC) method and by the classification strategy followed. p62-IHC staining yielded good uniform quality of stains, but the most reliable results were obtained implementing specific Abs directed against the hallmark protein TDP43. Both assessment of the type and the extent of lesions were influenced by the Abs and by the quality of stain. Assessment of the extent of the lesions yielded poor results repeatedly; thus, the extent of pathology should not be used in diagnostic consensus criteria. Whilst 31 neuropathologists typed 30 FTLD-TDP cases, inter-rater agreement ranged from 19 to 100 per cent, being highest when applying phosphorylated TDP43/IHC. The agreement was highest when designating Type C or Type A/B. In contrast, there was a poor agreement when attempting to separate Type A or Type B FTLD-TDP. In conclusion, we can expect that neuropathologist, independent of his/her familiarity with FTLD-TDP pathology, can identify a TDP43-positive FTLD case. The goal should be to state a Type (A, B, C, D) or a mixture of Types (A/B, A/C or B/C). Neuropathologists, other clinicians and researchers should be aware of the pitfalls whilst doing so. Agreement can be reached in an inter-laboratory setting regarding Type C cases with thick and long neurites, whereas the differentiation between Types A and B may be more troublesome.

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with approximately 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 x 10(-3)). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 x 10(-3)). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 x 10(-6)). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.

Human papillomavirus (HPV) is the necessary cause for cervical cancer development, and the interaction of HPV-E6 with p53 is known as the most important event in HPV-associated carcinogenesis. In vitro studies have suggested that HPV-E6 interacts more efficiently with the arginine (Arg) p53 variant at position 72 as it appears to be more susceptible to degradation through the ubiquitin proteasome pathway. However, few reports have corroborated this data, and the role of the p53 codon 72 polymorphism in the development of cervical cancer requires further elucidation. We performed a meta-analysis review of all studies published within European populations to summarize the overall risk of this polymorphism considering the influence of the geographical/ethnic location as an important factor in defining a genetic profile and the susceptibility for cervical cancer development. Our analysis revealed that the p53 Arg/Arg genotype does not seem to represent a risk marker for the development of cervical lesions in the majority of the European countries analysed. However, in countries with low incidence rates of cervical cancer, this polymorphism might represent a significant genetic marker.