Suzuki K, Elegheert J, Song I, Sasakura H, Senkov O, Matsuda K, Kakegawa W, Clayton AJ, Chang VT, Ferrer-Ferrer M, Miura E, Kaushik R, Ikeno M, Morioka Y, Takeuchi Y, Shimada T, Otsuka S, Stoyanov S, Watanabe M, Takeuchi K, Dityatev A, Aricescu AR, Yuzaki M. A synthetic synaptic organizer protein restores glutamatergic neuronal circuits. Science. 2020 Aug 28;369(6507) PubMed.
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The University of Tokyo
This is a very elegant and profound paper that introduces a new therapeutic concept to the field of neurological diseases. Based on previously known molecular neurobiological and structural information, the authors have successfully generated an artificial synaptic organizer molecule, CPTX, which restored synaptic and behavioral abnormalities in mouse models of Alzheimer’s disease (AD) and spinal cord injury (SCI).
Since mutations in genes encoding synaptic organizer molecules have been identified in psychiatric disorders, where neuronal death is not evident, these molecules have been studied mainly for their relationship to the function of existing synapses. The effectiveness of CPTX in AD and SCI models suggests that it may be possible to use synaptic organizers to induce synaptic recovery in neurodegenerative diseases as well. Considering further applications in therapeutics, it will be important to examine the feasibility of such treatments for neurodegeneration caused not just by extracellular toxins such as amyloid-β, but by intracellular aggregates such as tau, α-synuclein, and TDP-43.
The synaptic induction potency and stability of CPTX would be critical, as this synaptic organizer approach might not alter the formation/maintenance of such protein aggregates, which affect neuronal viability over long periods of time in people. Nevertheless, results of SCI model clearly indicate that CPTX is potent enough to induce synapses in a neurodegenerative condition. This study opens a new avenue for the treatment of neurological disorders.
View all comments by Taisuke TomitaUniversitat Autonoma Barcelona
Universitat Autònoma de Barcelona
A synthetic synaptic organizer protein restores glutamatergic neuronal circuits
This is a remarkable study that proposes the novel concept that a synthetic molecule that assembles pre- and postsynaptic regions in central synapses can promote the formation of active glutamatergic synapses and restore damaged neural circuits. Based on protein structural analysis, the researchers engineered a synaptic bridge protein (CPTX), consisting on key domains of extracellular synaptic proteins cerebellin-1 (Cbln1) and pentraxin-1 (NP1), that induces synapses in vitro and in vivo, and improves the function of excitatory synapses in mouse models of neurodegeneration. The investigation opens the possibility that molecules designed to potentiate synaptic connections could be useful as therapeutic drugs for synaptopathies, including neuropsychiatric and neurological disorders. The idea that therapeutics based on synapse recovery in neurological diseases is not novel, but this study represents certainly a proof of principle that potentiating synapse function could be useful to improve and/or recover memory and behavioral alterations in neurological and neurodegenerative diseases, including Alzheimer disease (AD) among others. In support of this idea, the authors demonstrate that injection of CPTX promotes synapse formation and functionality of neural circuits in AD (hippocampus), ataxia (cerebellum) and spinal cord injury (SCI) mouse models.
The beneficial effects of CPTX are observed only few days after treatment, suggesting a rapid recovery of functional synapses in the damaged regions. However, many relevant questions arise. For instance, which are the long-term CPTX effects of potentiating the number and/or function of synapses, particularly excitatory synapses, in memory and motor neural circuits? Could CPTX treatment lead to overexcitation and/or excitotoxicity resulting in further neurodegeneration? This question is important because increased synaptic excitability and excitatory/inhibitory imbalance has been associated with changes of brain activity at early stages of AD (Saura et al., 2015; Styr and Slutsky, 2018). The authors argue that, at least in vivo, CPTX increases and potentiates specifically excitatory glutamatergic synapses. However, and according to the study, CPTX not only increases postsynaptic GluA1-3 glutamate receptors in hippocampal neurons but also GluA4 in parvalbumin interneurons, which suggests effects on both excitatory and inhibitory synapses. Considering that neurexins and their ligands neuroligins, and Cbln isoforms, regulate inhibitory synaptic activity and other neurotransmitter systems (Südhof, 2008), adverse drug effects cannot ruled out. Future studies are needed to reveal the possible collateral pre- and postsynaptic effects of CPTX on key synapse homeostasis and mechanisms, including synaptic signaling, plasticity, synapse-to-cell signaling, etc. … The stability and side effects of these synthetic molecules may dictate their real use and effectiveness in future therapeutics.
An important challenge is to translate these interesting results to medical applications. Can these synthetic synaptic molecules, or similar extracellular scaffolding proteins, be effective for treating synapse dysfunction in brain disorders caused by different etiologies? Are they beneficial to restore damaged neural circuits in human neurodegenerative/injury (e.g., AD, SCI …) and developmental neuropsychiatric (e.g., autism, intellectual disability…) diseases? Could they improve brain function in non-pathological conditions? If this is the case, as suggested by the study, how do these treatments affect other classical pathological hallmarks of these neurological diseases, including neurodegeneration, neuroinflammation and accumulation of misfolded proteins? In order to be effective in the central nervous system, these synthetic "synapse bridge" molecules should cross the blood-brain barrier, target specific neural circuits and, ideally, modulate other classical disease hallmarks. Further developments may improve the design of future “synapse bridge” molecules, shedding light onto both the beneficial and adverse effects of potentiating glutamatergic neurotransmission in humans.
References:
Saura CA, Parra-Damas A, Enriquez-Barreto L. Gene expression parallels synaptic excitability and plasticity changes in Alzheimer's disease. Front Cell Neurosci. 2015;9:318. Epub 2015 Aug 25 PubMed.
Styr B, Slutsky I. Imbalance between firing homeostasis and synaptic plasticity drives early-phase Alzheimer's disease. Nat Neurosci. 2018 Apr;21(4):463-473. Epub 2018 Feb 5 PubMed.
Südhof TC. Neuroligins and neurexins link synaptic function to cognitive disease. Nature. 2008 Oct 16;455(7215):903-11. PubMed.
View all comments by Arnaldo Parra-DamasMake a Comment
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