The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects

Abstract

The Bridging Integrator 1 (BIN1) gene is a major genetic risk factor for Alzheimer's disease (AD) but little is known about its physiological functions. In addition, deciphering its potential pathophysiological role is difficult due to its numerous isoforms expressed in different cerebral cell types. Here we took advantage of a drosophila model to assess in vivo the impact of different BIN1 isoforms on neuronal toxicity: the neuronal isoform 1 (BIN1iso1), the muscular isoform 8 (BIN1iso8) and the ubiquituous isoform 9 (BIN1iso9). We showed that contrary to BIN1iso8 and BIN1iso9, BIN1iso1 overexpression induced neurodegeneration and an accumulation of vesicles mainly labeled by endosome markers. Systematic search for endosome trafficking regulators that are able to rescue BIN1iso1-induced neurodegeneration indicated a defect in the early endosome trafficking machinery. In human induced neurons and cerebral organoids, BIN1 knock-out resulted in narrowing of the early endosomes. This phenotype was rescued by BIN1iso1 expression but not that of BIN1iso9. Finally, in accordance with our previous observation in flies, we also observed that BIN1iso1 overexpression led to an increase in size of the early endosomes in human induced neurons. Altogether, our data demonstrate that the AD genetic risk factor BIN1, and especially BIN1iso1, contributes to early-endosome size deregulation which is a very early pathophysiological feature observed in AD pathogenesis.

The role of Alzheimer's disease risk genes in endolysosomal pathways

“…( Miyagawa et al, 2016 ). Interestingly, studies in human neurons report that BIN1 overexpression resulted in increased EE size and loss of BIN1 resulted in decreased EE size( Lambert et al, 2021 )(). Taken together, these studies suggest that the role of BIN1 , although different in rodents and humans, is crucial in regulating ELN function in neurons especially at the level of EEs.…”

Application of Fluorescent Proteins for Functional Dissection of the Drosophila Visual System

“…This report demonstrated that while Rh1 phosphorylation was not required for interaction with Arr2::GFP, it appeared to be needed for internalization of Rh1/Arr2 complexes and thus to be partially responsible for retinal degeneration in norpA P24 mutants. In a work utilizing the Drosophila eye as a model for Alzheimer's disease, both Rh1::GFP as well as GFP::NINAC were utilized as rhabdomeral markers to record retinal degeneration [50]. Lambert et al reported dysregulation of the endosomal trafficking machinery by the neuronally expressed isoform 1 of the genetic risk factor BIN1.…”

“…Fluorescently tagged phosphoinositide-binding domains additionally serve another purpose in cell biological questions. Due to PI(3)P's significant enrichment in early endosomal structures, GFP::2xFYVE is routinely used as a subcellular marker, especially for studies regarding vesicular trafficking including investigations in the Drosophila eye [50,112].…”