The p75 neurotrophin receptor (p75 NTR ) is a member of the tumour necrosis factor superfamily, which relies on the recruitment of cytosolic protein partners including the tumour necrosis factor receptor-associated factor 6 (TRAF6) E3 ubiquitin ligase to produce cellular responses. Recently, p75 NTR was also shown to undergo presenilin-dependent, csecretase-mediated regulated intramembrane proteolysis. In this study, we report the characterization of a highly conserved TRAF6-binding site (PxExxAr/Ac) in presenilin-1 (PS1) that mediates nerve growth factor (NGF)-induced association between PS1 and TRAF6. We demonstrate that disruption of this interaction between PS1 and TRAF6 inhibits TRAF6 autoubiquitination and c-secretase cleavage of p75 NTR .Additionally, we show that PS1-deficiency antagonizes NGFinduced I-jB degradation. Finally, we also show that p75 NTR is a substrate for TRAF6-mediated ubiquitination and that TRAF6 E3 ligase activity is required for regulated intramembrane proteolysis of p75 NTR . In summary, our data suggest that an NGF-induced association between PS1 and TRAF6 influences regulated intramembrane proteolysis of p75 NTR .

The COVID-19 pandemic has disrupted neurosurgical training worldwide, with the shutdown of academic institutions and the reduction of elective surgical procedures. This impact has disproportionately affected LMICs (lower- and/or middle-income countries), already burdened by a lack of neurosurgical resources. Thus, a systematic review was conducted to examine these challenges and innovations developed to adapt effective teaching and learning for medical students and neurosurgical trainees. A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) and The Cochrane Handbook of Systematic Reviews of Interventions. MEDLINE, PubMed, Embase and Cochrane databases were accessed, searching and screening literature from December 2019 to 5th December 2020 with set inclusion and exclusion criteria. Screening identified 1254 articles of which 26 were included, providing data from 96 countries. Twenty-three studies reported transition to online learning, with 8 studies also mentioned redeployment into COVID wards with 2 studies mentioning missed surgical exposure as a consequence. Of 7 studies conducted in LMICs, 3 reported residents suffering financial insecurities from reduced surgical caseload and recession. Significant global disruption in neurosurgical teaching and training has arisen from the COVID-19 pandemic. Decreased surgical exposure has negatively impacted educational provision. However, advancements in virtual technology have allowed for more affordable, accessible training especially in LMICs. Using this, initiatives to reduce physical and mental stress experienced by trainees should be paramount.

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