Figure 5.

Hub-Connector Knockdowns Rescue Age-Dependent Chemotaxis Decline

(A) SY5Y-APP_Sw interactome showing the distribution of hub connectors (green dots) across the network. Insets show the local contactomes of six hub proteins: SERF2 (small EDRK-rich factor 2 [Balasubramaniam et al., 2018]); PP1A (α catalytic subunit of protein phosphatase 1, PP1, a serine/threonine protein phosphatase involved in cardiac function, learning, and memory); DRG1 (developmentally regulated GTP-binding protein 1, expressed in neural precursor cells); ACTN1 (actinin α1, a cytoskeletal protein related to spectrins and dystrophins); RPS5 (ribosomal protein S5); and COPG1 (coatomer complex subunit γ1, required for budding from Golgi membranes and for retrograde Golgi-to-ER transport of dilysine-tagged proteins).

(B) Rescue of age-dependent chemotaxis loss, by knockdown of hub connectors in C. elegans strain CL2355 (uninduced, pan-neuronal Aβ₄₂ expression). Results are shown for three independent experiments (different-colored bars). *p < 0.04 by one-tailed paired t test, comparing each knockdown to its corresponding, simultaneous FV control.

(C) Computational model of ATRX interacting weakly but directly with PPIG (ΔE_interaction = −73.2 kcal/mol).

(D) Computational model of ATRX interacting strongly with PPIG via the hub connector RPS5 (ΔE_interaction = −120.9 kcal/mol).