Design and Synthesis of Fluorescent Methylphenidate Analogues for a FRET‐Based Assay of Synapsin III Binding

Casiraghi, Andrea; Longhena, Francesca; Straniero, Valentina; Faustini, Gaia; Newman, Amy Hauck; Bellucci, Arianna; Valoti, Ermanno

doi:10.1002/cmdc.202000128

Cited by 11 publications

(13 citation statements)

References 26 publications

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“…Interestingly, we previously demonstrated that Syn III ko mice do not present motility improvement following acute i.p. administration of MPH [ 11 , 12 ], in agreement with our findings supporting that MPH can bind Syn III and with evidence showing that the efficacy of MPH is perturbed in ADHD patients with Syn III polymorphisms [ 10 , 12 ]. Still, consistently with the reduction of cocaine-induced facilitation of DA release in SN pr brain slices from Syn III-deficient mice [ 1 ], we also found that these animals do not even present a locomotor response following acute cocaine administration [ 11 ].…”

Section: Discussionsupporting

confidence: 91%

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Synapsin III Regulates Dopaminergic Neuron Development in Vertebrates

Faustini

Longhena

Muscò

et al. 2022

Cells

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Attention deficit and hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by alterations in the mesocorticolimbic and nigrostriatal dopaminergic pathways. Polymorphisms in the Synapsin III (Syn III) gene can associate with ADHD onset and even affect the therapeutic response to the gold standard ADHD medication, methylphenidate (MPH), a monoamine transporter inhibitor whose efficacy appears related with the stimulation of brain-derived neurotrophic factor (BDNF). Interestingly, we previously showed that MPH can bind Syn III, which can regulate neuronal development. These observations suggest that Syn III polymorphism may impinge on ADHD onset and response to therapy by affecting BDNF-dependent dopaminergic neuron development. Here, by studying zebrafish embryos exposed to Syn III gene knock-down (KD), Syn III knock-out (ko) mice and human induced pluripotent stem cells (iPSCs)-derived neurons subjected to Syn III RNA interference, we found that Syn III governs the earliest stages of dopaminergic neurons development and that this function is conserved in vertebrates. We also observed that in mammals Syn III exerts this function acting upstream of brain-derived neurotrophic factor (BDNF)- and cAMP-dependent protein kinase 5 (Cdk5)-stimulated dendrite development. Collectively, these findings own significant implications for deciphering the biological basis of ADHD.

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Section: Discussionsupporting

confidence: 91%

“…Interestingly, certain human Syn III gene (SYN3) polymorphisms associate with ADHD onset and influence the response to the most effective ADHD treatment, methylphenidate (MPH), a monoamine reuptake inhibitor which binds Syn III [ 4 , 10 , 11 , 12 ]. This hints that Syn III may control the development of mDN.…”

Section: Introductionmentioning

confidence: 99%

Synapsin III Regulates Dopaminergic Neuron Development in Vertebrates

Faustini

Longhena

Muscò

et al. 2022

Cells

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“…administration of MPH, consistently with ndings showing that the action of this drug can be mediated by Syn III [12,13].…”

Section: Discussionsupporting

confidence: 83%

“…Certain human Syn III gene polymorphisms associate with ADHD onset and can even in uence the response to the most effective ADHD treatment, methylphenidate (MPH), a key modulator of dopaminergic neurotransmission that, as we recently showed, can bind Syn III [9,[11][12][13]. ADHD is characterized by an impaired development of dopaminergic neurons, re ected by a marked alteration in brain dopamine (DA) synthesis and dopaminergic dysregulations [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Synapsin III Controls Early Phases of Dopaminergic Neurons Development in Fishes and Mammals by Acting Upstream of BDNF and Cdk5 Signaling

Faustini

Longhena

Muscò

et al. 2021

Preprint

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Polymorphisms in the Synapsin III (Syn III) gene can associate with attention deficits and hyperactivity disorder (ADHD), a neurodevelopmental disorder characterized by alterations in the mesocorticolimbic and nigrostriatal dopaminergic pathways. In spite of evidence supporting that Syn III controls the development of cortical and hippocampal short-projecting neurons, whether it plays a similar role in midbrain dopaminergic neurons (mDN), owning extensively arborized long-distance multi-synaptic axonal projections, was unexplored. Our studies on mDN development in zebrafish embryos exposed to Syn III gene knock-down (KD), Syn III knock-out (ko) mice and Syn III-deleted human induced pluripotent stem cells (iPSCs)-derived neurons disclose that Syn III governs early mDN developmental stages in fishes and mammals. Differently to what observed in cortical and hippocampal neurons, this Syn III function impinges on the upstream control of brain derived neurotrophic factor (BDNF)-mediated and cAMP-dependent protein kinase 5 (Cdk5)-stimulated dendrite development. These findings have significant implications for deciphering the basis of ADHD.

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“…10 Consistently, by generating a fluorescent cell permeable MPH derivative, we were able to detect a direct interaction between MPH and Syn III in cells in culture by fluorescence resonance energy transfer (FRET). 14 In addition, we observed that MPH promotes the interaction between Syn III and a specific a-helical conformation of a-syn owning low aggregation propensity. 10 This effect is contrary to that of Syn III, which instead appears to promote a-syn aggregation.…”

Section: Introductionmentioning

confidence: 72%

Synapsin III gene silencing redeems alpha-synuclein transgenic mice from Parkinson's disease-like phenotype

et al. 2022

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Fibrillary aggregated a-synuclein (a-syn) deposition in Lewy bodies (LB) characterizes Parkinson's disease (PD) and is believed to trigger dopaminergic synaptic failure and a retrograde terminal-to-cell body neuronal degeneration. We described that the neuronal phosphoprotein synapsin III (Syn III) cooperates with a-syn to regulate dopamine (DA) release and can be found in the insoluble a-syn fibrils composing LB. Moreover, we showed that a-syn aggregates deposition, and the associated onset of synaptic deficits and neuronal degeneration occurring following adeno-associated viral vectors-mediated overexpression of human a-syn in the nigrostriatal system are hindered in Syn III knock out mice. This supports that Syn III facilitates a-syn aggregation. Here, in an interventional experimental design, we found that by inducing the gene silencing of Syn III in human a-syn transgenic mice at PD-like stage with advanced a-syn aggregation and overt striatal synaptic failure, we could lower a-syn aggregates and striatal fibers loss. In parallel, we observed recovery from synaptic vesicles clumping, DA release failure, and motor functions impairment. This supports that Syn III consolidates a-syn aggregates, while its downregulation enables their reduction and redeems the PD-like phenotype. Strategies targeting Syn III could thus constitute a therapeutic option for PD.

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Design and Synthesis of Fluorescent Methylphenidate Analogues for a FRET‐Based Assay of Synapsin III Binding

Cited by 11 publications

References 26 publications

Synapsin III Regulates Dopaminergic Neuron Development in Vertebrates

Synapsin III Regulates Dopaminergic Neuron Development in Vertebrates

Synapsin III Controls Early Phases of Dopaminergic Neurons Development in Fishes and Mammals by Acting Upstream of BDNF and Cdk5 Signaling

Synapsin III gene silencing redeems alpha-synuclein transgenic mice from Parkinson's disease-like phenotype

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