SERF deletion modifies amyloid aggregation in a mouse model of Alzheimer’s disease

Abstract

Neurodegenerative diseases like Alzheimer, Parkinson and Huntington disease are characterized by aggregation-prone proteins that form amyloid fibrils through a nucleation process. Despite the shared β-sheet structure, recent research has shown that structurally different polymorphs exist within fibrils of the same protein. These polymorphs are associated with varying levels of toxicity and different disease phenotypes. MOAG-4 and its human orthologs SERF1 and SERF2 have previously been shown to modify the nucleation and drive amyloid formation and protein toxicity in vitro and in C. elegans. To further explore these findings, we generated a Serf2 knockout (KO) mouse model and crossed it with the APPPS1 mouse model for Aβ amyloid pathology. Full-body KO of Serf2 resulted in a developmental delay and perinatal lethality due to insufficient lung maturation. Therefore, we proceeded with a brain-specific Serf2 KO, which was found to be viable. We examined the Aβ pathology at 1 and 3 months of age, which is before and after the start of amyloid deposition. We show that SERF2 deficiency does not affect the production and overall Aβ levels. Serf2 KO-APPPS1 mice displayed an increased intracellular Aβ accumulation at 1 month and a higher number of Aβ deposits compared to APPPS1 mice with similar Aβ levels. Moreover, conformation-specific dyes and electron microscopy revealed a difference in the structure and amyloid content of these Aβ deposits. Together, our results reveal that SERF2 causes a structural shift in Aβ aggregation in a mammalian brain. These findings indicate that a single endogenous factor may contribute to amyloid polymorphisms, allowing for new insights into this phenomenon’s contribution to disease manifestation.HighlightsLoss of SERF2 slows embryonic development and causes perinatal lethalitySERF2 affects proliferation in a cell-autonomous fashionBrain-specific Serf2 knockout does not affect viability or Aβ productionBrain deletion of Serf2 shifts the amyloid conformation of Aβ

SERF, a family of tiny highly conserved, highly charged proteins with enigmatic functions

“…Although the pathology‐associated function of SERF‐linked species may well be related to its ability to facilitate amyloid formation, if SERF is important for neural‐specific amyloid formation, one might expect brain‐specific SERF knockouts to exhibit differences in amyloid formation within neural tissues when amyloid prone proteins are expressed there. A mouse SERF knockout is reported to alter intracellular Aβ accumulation and is shown to have a higher plaque deposition when relative to a wild‐type mouse [86]. Although minor differences in amyloid's dye‐binding characteristics have been observed, change in Aβ production, or the Aβ levels or processing of the amyloid precursor protein have not been observed [86].…”

“…A mouse SERF knockout is reported to alter intracellular Aβ accumulation and is shown to have a higher plaque deposition when relative to a wild‐type mouse [86]. Although minor differences in amyloid's dye‐binding characteristics have been observed, change in Aβ production, or the Aβ levels or processing of the amyloid precursor protein have not been observed [86]. Whole‐body SERF knockouts in C57BL/6 N background mice are perinatally lethal and show developmental defects including behavioural and neurological deficits in mice implying that SERF does play an important role in development; however, the connection of these observations to SERF's role in amyloid formation and pathology of neurodegenerative diseases is still unclear [87].…”

Polymorphism of SERF2, the gene encoding a heat-resistant obscure (Hero) protein with chaperone activity, is a novel link in ischemic stroke

“…Previously, SERF2 was reported to enhance polyglutamine, β-amyloid and α-Synuclein aggregation and to contribute to amyloid proteotoxicity ( [49] , [17] , [33] ). Moreover, brain-specific Serf2 knockout mice, though viable, appear to be more prone to deposition of amyloids, and show modified fibril morphology ( Stroo et al, 2021 ). Whole-body knockouts are perinatally lethal due to an apparently unrelated developmental issue ( Cleverley et al, 2021 ).…”

A tale of dual functions of SERF family proteins in regulating amyloid formation

“…Its absence delays cell growth, underscoring its critical role in cell growth and development. [32] ScSERF is the yeast Saccharomyces cerevisiae's homolog of MOAG-4 and is present in yeast at a concentration of 143 ppm (parts per million). [33] ScSERF can influence the primary nucleation processes of Aβ40 and α-synuclein.…”