Abstract A recent publication by Xu et al. suggests that Gi activation following 5-HT2AR stimulation differentiates hallucinogenic from nonhallucinogenic agonists. Here, we reanalyze the author’s source data to demonstrate that Gi activation is less predictive of hallucinogenic potential than canonical effectors of 5-HT2AR signaling.
Abstract Neurodegenerative diseases comprise a collection of disorders that systematically bring about the death of a variety of cell types within the brain, resulting in cognitive and/or motor impairments that gradually decrease the quality of life until eventual death. While each disease possesses its own unique phenotype, many neurodegenerative diseases share the same pathologic etiology. However, an understudied aspect of neurodegenerative diseases is depleted neurotrophic signaling. Under healthy conditions, neurotrophins promote cell survival through the activation of neurite formation, neurogenesis, cytoskeletal rearrangement, and long-term potentiation. Given the multitude of cellular benefits of neurotrophins, targeting their signaling pathways may facilitate neurodegenerative disease therapy development. In this Review, we examine various neurodegenerative diseases and how they may benefit from tropomyosin receptor kinase B/brain-derived neurotrophic factor (TrkB/BDNF)-targeted therapies. The molecular mechanisms of neurotrophin signaling that contribute to neuronal survival are discussed, and a comprehensive overview of experimentally validated small molecules that exhibit neuroprotective effects by modulating the TrkB/BDNF signaling pathway in neurodegenerative diseases is provided.
Current research into the actions of psychedelic drugs is focused on 5-HT2A receptor-coupled signaling pathways, particularly beta-arrestin2 signaling. Here, we investigated the involvement of beta-arrestin2 in psychedelic drug-induced mouse markers of hallucinogenic effects, molecular plasticity, and structural plasticity; specifically, the head-twitch response, cortical expression of plasticity-related genes (cFos, Egr1, Egr2, and Arc), and dendritogenesis (primary cortical neuron cultures), respectively. Psilocin-induced head-twitches, plasticity gene expression, and dendritogenesis were all blocked by the 5-HT2A receptor antagonist MDL-100,907. The head-twitch response to psilocin was not different between wildtype and beta-arrestin2 knockout (KO) mice, and the head-twitch responses to 2,5-dimethoxy-4-iodoamphetamine (DOI) and lysergic acid diethylamide (LSD) were similarly unaffected by beta-arrestin2 KO. Psilocin-evoked gene expression showed a trend to be less in beta-arrestin2 KO compared to wildtype mice, but the gene expression response to DOI was clearly not altered by beta-arrestin2 KO. Finally, psilocin-induced dendritogenesis was attenuated in beta-arrestin2 KO versus wild-type cultured neurons, and similar findings were obtained with DOI. In summary, the current study found no convincing evidence to support a role for beta-arrestin2 signaling in either the head-twitch or plasticity-related gene responses to the psychedelic drugs tested. However, our data suggest a role for the beta-arrestin2 pathway in psychedelic drug-evoked dendritogenesis of cultured neurons. Thus, the beta-arrestin2 pathway unlikely mediates the hallucinogenic effects of psychedelic drugs but may contribute to neural plasticity changes in certain models.
Carriers of the fragile X messenger ribonucleoprotein 1 (FMR1) gene have an elevated risk of developing Fragile X-associated tremor/ataxia syndrome (FXTAS), a progressive late-onset neurodegenerative disorder. Expansion of CGG trinucleotide repeats within the 5' untranslated region leads to RNA-mediated toxicity and promotes the aggregation of toxic FMR1polyglycine (FMR1polyG), driving neuronal dysfunction and degeneration. Yet, effective therapies that alter disease progression remain lacking. In this study, we evaluated a drug repurposing strategy to modulate FXTAS pathogenesis by targeting CGG repeat RNA structures using Itraconazole (ITZ), a clinically approved antifungal, in combination with Lacosamide (LCM), an established antiepileptic drug. The ITZ+LCM combination significantly reduced FMR1polyG aggregation and attenuated oxidative stress and cell death in an in vivo model of FXTAS. Notably, this combination also improved locomotor performance and extended the lifespan of model flies, with a fourfold reduction in the effective ITZ dose. These findings were further validated at the cellular level using (CGG)99 transfected HEK293T and COS-7 cells, wherein the ITZ+LCM treatment suppressed FMR1polyG aggregation and corrected CGG repeat splicing defects. Biophysical studies revealed the selective interaction of the drug combination with CGG-expanded RNA. These findings identify the ITZ+LCM combination as a promising, clinically translatable therapeutic strategy against FXTAS to counter RNA-mediated neurotoxicity.
The misfolding of human islet amyloid polypeptide (hIAPP) into soluble oligomers is a primary pathological event in type 2 diabetes, with the early dimerization process representing a critical pharmacological target. Here, we investigate the molecular mechanism by which rosmarinic acid (RA) counteracts full-length hIAPP self-association through replica-exchange molecular dynamics. Our results show that RA drastically suppresses overall beta-sheet propensities and truncates extended, aggregation-competent beta-strands, lowering the sampled population of ordered beta-hairpin-like motifs associated with amyloidogenic hIAPP conformations. Instead of forming compact structures, the hIAPP dimer is diverted toward disordered, hyper-solvated topologies. This conformational remodeling is driven by spatially heterogeneous thermodynamic perturbations that disrupt native interpeptide contacts and transfer structured motifs into localized turn and bend structures at the C-terminus. Energetically, RA outcompetes peptide-peptide interactions via a multimodal strategy, preferentially anchoring to the hIAPP N-terminus through residues K1 and R11 while simultaneously engaging the hydrophobic core via pi-pi stacking. Notably, this robust noncovalent occupation of key amyloidogenic regions occurs spontaneously in the simulations, offering an atomistic clue for modulating early hIAPP self-association. These structural and energetic insights clarify how RA interacts with transient hIAPP dimer ensembles, providing a defined biophysical framework for the rational design of amyloid inhibitors.
