Premium
Isoform‐dependent neurotoxicity of the Alzheimer disease risk factor BIN1
Author(s) -
Lambert Erwan,
Abdelfettah Farida,
Barois Nicolas,
Vandekerkhove Dirk,
Hermant Xavier,
Ayral AnneMarie,
Davoine Lindsay,
Dupont Cloe,
Lafont Frank,
Amouyel Philippe,
Chapuis Julien,
Verstreken Patrik,
Dermaut Bart,
Lambert JeanCharles,
Dourlen Pierre
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.039402
Subject(s) - endosome , neurotoxicity , neurodegeneration , gene isoform , lysosome , microbiology and biotechnology , biology , endocytic cycle , gene knockdown , endocytosis , biochemistry , cell culture , intracellular , receptor , pathology , toxicity , genetics , medicine , disease , gene , enzyme
Background Using genome‐wide association studies, BIN1 was identified as the most associated risk gene for Alzheimer’s Disease (AD) after APOE . A 3bp insertion allele was shown to increase BIN1 expression in human brains and AD risk. BIN1 has more than 10 isoforms and the contribution of BIN1 and its isoforms to AD pathogenesis remains unclear. The aim of this work was to assess the neurotoxicity of BIN1 isoforms and understand the underlying mechanisms. Method We generated Drosophila transgenic lines expressing brain, muscular and ubiquitous human BIN1 isoforms 1, 8 and 9 respectively. We analyzed BIN1 isoform neurotoxicity using cornea neutralization, immunofluorescence, electrophysiology and electron microscopy in the fly eye photoreceptor neurons. Result We showed that adult eye‐specific expression of the brain BIN1 isoform 1 (BIN1‐1) resulted in an age‐dependent loss of photoreceptor neurons. Interestingly, the effect was specific of this isoform only. We tested truncated BIN1‐1 forms and showed that the BIN1‐1‐specific CLAP domain is necessary for the BIN1‐1 induced neurodegeneration. This domain is involved in endocytosis and vesicular trafficking. In addition, photoreceptor neuron degeneration was characterized by a strong accumulation of vesicles with endosomal markers suggesting a blockade of the endosome‐lysosome pathway. We further found that modulation of Rab5, Rab4 and Rab11, involved at the level of the early and recycling endosomes, abrogated photoreceptor degeneration, indicating that BIN1‐1 toxicity is due to the blockade of the endosome‐lysosome pathway likely at the level of early endosomes. Finally, as endosomes are involved in synaptic vesicles formation and postsynaptic receptor recycling, we tested the electrophysiological consequences of BIN1‐1 expression. Although not affected in young flies, we observed that expression of BIN1‐1 affected early photoreceptor neuron synaptic transmission. Conclusion Altogether, these results show that an increase of the BIN1 isoform 1 impairs the endosome‐lysosome pathway, thereby affecting synaptic transmission and inducing neurodegeneration. Interestingly, enlarged endosomes have been shown to be one of the first cytopathological markers of the disease and synaptic transmission is affected early in AD pathogenesis. These results suggest that an increase in BIN1 isoform1 could contribute to early steps of Alzheimer’s disease.