2020
Alzheimer's Disease GWAS Risk Factor BIN1 Regulates Presynaptic Neurotransmitter Release and Memory Consolidation
Pierre De Rossi, Toshihiro Nomura, Robert J. Andrew, Nicolas Y. Masse, Vandana Sampathkumar, Timothy F. Musial, Ari Sudwarts, Aleksandra J. Recupero, Thomas Le Metayer, Mitchell T. Hansen, Ha-Na Shim, Sofia V. Krause, David J. Freedman, Vytas P. Bindokas, Narayanan Kasthuri, Daniel A. Nicholson, Anis Contractor, and Gopal Thinakaran.
Abstract: BIN1, a member of the BAR adaptor protein family, is a significant late-onset Alzheimer disease risk factor. Here, we investigate BIN1 function in the brain using conditional knockout (cKO) models. Loss of neuronal Bin1 expression results in the select impairment of spatial learning and memory. Examination of hippocampal CA1 excitatory synapses reveals a deficit in presynaptic release probability and slower depletion of neurotransmitters during repetitive stimulation, suggesting altered vesicle dynamics in Bin1 cKO mice. Super-resolution and immunoelectron microscopy localizes BIN1 to presynaptic sites in excitatory synapses. Bin1 cKO significantly reduces synapse density and alters presynaptic active zone protein cluster formation. Finally, 3D electron microscopy reconstruction analysis uncovers a significant increase in docked and reserve pools of synaptic vesicles at hippocampal synapses in Bin1 cKO mice. Our results demonstrate a non-redundant role for BIN1 in presynaptic regulation, thus providing significant insights into the fundamental function of BIN1 in synaptic physiology relevant to Alzheimer disease.
Phase Separation and Neurodegenerative Diseases: A Disturbance in the Force
Aurélie Zbinden, Manuela Pérez-Berlanga, Pierre De Rossi, Magdalini Polymenidou.
Abstract: Protein aggregation is the main hallmark of neurodegenerative diseases. Many proteins found in pathological inclusions are known to undergo liquid-liquid phase separation, a reversible process of molecular self-assembly. Emerging evidence supports the hypothesis that aberrant phase separation behavior may serve as a trigger of protein aggregation in neurodegeneration, and efforts to understand and control the underlying mechanisms are underway. Here, we review similarities and differences among four main proteins, α-synuclein, FUS, tau, and TDP-43, which are found aggregated in different diseases and were independently shown to phase separate. We discuss future directions in the field that will help shed light on the molecular mechanisms of aggregation and neurodegeneration.
https://doi.org/10.1016/j.devcel.2020.09.014
PMID: 33049211