Hamidreza Shaye

All Publications

• Aggregation shifts amyloid-β peptides from synaptogenic to synaptotoxic. The Journal of clinical investigation Siddu, A., Natale, S., Wong, C. H., Shaye, H., Südhof, T. C. 2025

  Abstract

  Whether amyloid-β (Aβ) peptides are synaptogenic or synaptotoxic remains a pivotal open question in Alzheimer's disease research. Here, we chronically treated human neurons with precisely controlled concentrations of chemically defined synthetic Aβ40, Aβ42, and Aβ42arctic peptides that exhibit distinct aggregation propensities. Remarkably, chronic exposure of human neurons to free Aβ40 at higher concentrations or to free Aβ42 at lower concentrations potently promoted synapse formation. In contrast, aggregated Aβ42 or Aβ42arctic at higher concentrations were neurotoxic and synaptotoxic. The synaptotoxic effects of Aβ peptides manifested as an initial contraction of the synaptic vesicle cluster followed by synapse loss. Aβ40 and Aβ42 peptides with scrambled or inverted sequences were inactive. Thus, our experiments reveal that Aβ peptides exhibit an aggregation-dependent functional dichotomy that renders them either synaptogenic or synaptotoxic, thereby providing insight into how Aβ peptides straddle a thin line between physiological synapse organization and pathological synapse disruption. Among others, our data suggest that Alzheimer's disease therapies might aim to shift the balance of Aβ peptides from the aggregated to the free state instead of suppressing all Aβ peptides.

  View details for DOI 10.1172/JCI193407

  View details for PubMedID 41026542

• Structural basis of GABA reuptake inhibition. Nature Motiwala, Z., Aduri, N. G., Shaye, H., Han, G. W., Lam, J. H., Katritch, V., Cherezov, V., Gati, C. 2022

  Abstract

  gamma-Aminobutyric acid (GABA) transporter 1 (GAT1)1 regulates neuronal excitation of the central nervous system by clearing the synaptic cleft of the inhibitory neurotransmitter GABA upon its release from synaptic vesicles. Elevating the levels of GABA in the synaptic cleft, by inhibiting GABA reuptake transporters, is an established strategy to treat neurological disorders, such as epilepsy2. Here we determined the cryo-electron microscopy structure of full-length, wild-type human GAT1 in complex with its clinically used inhibitor tiagabine3, with an ordered part of only 60kDa. Our structure reveals that tiagabine locks GAT1 in the inward-open conformation, by blocking the intracellular gate of the GABA release pathway, and thus suppresses neurotransmitter uptake. Our results provide insights into the mixed-type inhibition of GAT1 by tiagabine, which is an important anticonvulsant medication. Its pharmacodynamic profile, confirmed by our experimental data, suggests initial binding of tiagabine to the substrate-binding site in the outward-open conformation, whereas our structure presents the drug stalling the transporter in the inward-open conformation, consistent with a two-step mechanism of inhibition4. The presented structure of GAT1 gives crucial insights into the biology and pharmacology of this important neurotransmitter transporter and provides blueprints for the rational design of neuromodulators, as well as moving the boundaries of what is considered possible in single-particle cryo-electron microscopy of challenging membrane proteins.

  View details for DOI 10.1038/s41586-022-04814-x

  View details for PubMedID 35676483

• Structural basis of the activation of a metabotropic GABA receptor. Nature Shaye, H. n., Ishchenko, A. n., Lam, J. H., Han, G. W., Xue, L. n., Rondard, P. n., Pin, J. P., Katritch, V. n., Gati, C. n., Cherezov, V. n. 2020

  Abstract

  Metabotropic γ-aminobutyric acid receptors (GABAB) are involved in the modulation of synaptic responses in the central nervous system and have been implicated in neuropsychological conditions that range from addiction to psychosis1. GABAB belongs to class C of the G-protein-coupled receptors, and its functional entity comprises an obligate heterodimer that is composed of the GB1 and GB2 subunits2. Each subunit possesses an extracellular Venus flytrap domain, which is connected to a canonical seven-transmembrane domain. Here we present four cryo-electron microscopy structures of the human full-length GB1-GB2 heterodimer: one structure of its inactive apo state, two intermediate agonist-bound forms and an active form in which the heterodimer is bound to an agonist and a positive allosteric modulator. The structures reveal substantial differences, which shed light on the complex motions that underlie the unique activation mechanism of GABAB. Our results show that agonist binding leads to the closure of the Venus flytrap domain of GB1, triggering a series of transitions, first rearranging and bringing the two transmembrane domains into close contact along transmembrane helix 6 and ultimately inducing conformational rearrangements in the GB2 transmembrane domain via a lever-like mechanism to initiate downstream signalling. This active state is stabilized by a positive allosteric modulator binding at the transmembrane dimerization interface.

  View details for DOI 10.1038/s41586-020-2408-4

  View details for PubMedID 32555460