Deletion of SERF2 in mice delays embryonic development and alters amyloid deposit structure in the brain

Abstract

In age-related neurodegenerative diseases, like Alzheimer’s and Parkinson’s, disease-specific proteins become aggregation-prone and form amyloid-like deposits. Depletion of SERF proteins ameliorates this toxic process in worm and human cell models for diseases. Whether SERF modifies amyloid pathology in mammalian brain, however, has remained unknown. Here, we generated conditionalSerf2knockout mice and found that full-body deletion ofSerf2delayed embryonic development, causing premature birth and perinatal lethality. Brain-specificSerf2knockout mice, on the other hand, were viable, and showed no major behavioral or cognitive abnormalities. In a mouse model for amyloid-β aggregation, brain depletion ofSerf2altered the binding of structure-specific amyloid dyes, previously used to distinguish amyloid polymorphisms in the human brain. These results suggest thatSerf2depletion changed the structure of amyloid deposits, which was further supported by scanning transmission electron microscopy, but further study will be required to confirm this observation. Altogether, our data reveal the pleiotropic functions of SERF2 in embryonic development and in the brain and support the existence of modifying factors of amyloid deposition in mammalian brain, which offer possibilities for polymorphism-based interventions.

The disordered protein SERF promotes α-Synuclein aggregation through liquid–liquid phase separation

“…Importantly, distinguished from the conventional mechanisms, SERF decreases the α-Syn aggregation toxicity through attenuating the accumulation of the more toxic α-Syn oligomer species, which might serve as a novel mechanism of intracellular self-protection. A recent study ( 44 ) suggested that the brain depletion of SERF2 altered the structure of amyloid-β deposits. However, there was no compensatory upregulation of SERF1 in response to SERF2 knockout, which provides a direction for our forthcoming work.…”

Backbone 1H, 13C, and 15N chemical shift assignments for human SERF2

“…SERF2 has been shown in a peptide microarray analysis to bind many amyloidogenic peptide sequences (Pras et al 2021). SERF2 function has also been shown to be linked with developmental de cits and embryonic lethality (Cleverley et al 2021;Stroo et al 2023). While the pathological role of SERF2 is reasonably well established, its physiological function(s) remain poorly explored, though it has recently been shown to bind nucleic acids, particularly G4 quadruplex forming sequences (Sahoo et al 2023).…”