Overview

• In PNAS, Rockefeller University researchers report that modest PI31 overexpression prevented neuronal loss and restored motor and synaptic function in FBXO7-deficient flies and mice.
• PI31 serves as an adaptor that loads proteasomes onto cellular motors for transport to synapses, enabling local clearance of protein waste.
• In mouse models, boosting PI31 reduced abnormal tau accumulation and, in some cases, extended lifespan nearly fourfold with broad health benefits.
• The findings support a shift away from an amyloid-centric view by indicating that visible protein aggregates likely arise downstream of failed synaptic proteostasis.
• Next steps include testing cognitive preservation in aging mice and pursuing preclinical development, with human relevance suggested by a preprint linking rare PI31 mutations to neurodegenerative conditions.