De‐palmitoylation by N‐(tert‐Butyl) hydroxylamine inhibits <scp>AMPAR</scp>‐mediated synaptic transmission via affecting receptor distribution in postsynaptic densities

Xia, Zhi-Xuan; Shen, Zu-Cheng; Zhang, Shao-Qi; Ji, Wang; Nie, Tai-Lei; Deng, Qiao; Chen, Jianguo; Wang, Fang; Wu, Pengfei

doi:10.1111/cns.12996

Cited by 9 publications

(9 citation statements)

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“…We here demonstrated that blocking neuronal activity with TTX to simulate increased transmission strength in synaptic network enhanced the global palmitoylation and PSD-95 and glutamate receptor palmitoylation levels, as well as the synaptic and membrane surface distribution of these PSD proteins. Consistent with our previous results (Shen et al, 2019;Xia et al, 2019), treating with palmitoylation inhibitors, 2-BP or NtBuHA, reversed the increased palmitoylation levels or synaptic expression of the target molecules, such as PSD-95, GluA1-2, and NMDARs. Additionally, depalmitoylation plays a pivotal role in recycling and/or degradation of proteins that undergo palmitoylation (Greaves and Chamberlain, 2007;Salaun et al, 2010); and in clinical research, analysis of the brains of patients with infantile neuronal ceroid lipofuscinosis compared with control samples revealed an obvious deficiency of PPT1, which impairs the cleavage of thioester linkage in palmitoylated proteins, and prevents the degradation and causes accumulation of lysosomal ceroid (Kim et al, 2008;Sarkar et al, ).…”

Section: Discussionsupporting

confidence: 92%

APT1-Mediated Depalmitoylation Regulates Hippocampal Synaptic Plasticity

et al. 2022

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Palmitoylation may be relevant to the processes of learning and memory, and even disorders, such as post-traumatic stress disorder and aging-related cognitive decline. However, underlying mechanisms of palmitoylation in these processes remain unclear. Herein, we used acyl-biotin exchange, coimmunoprecipitation and biotinylation assays, and behavioral and electrophysiological methods, to explore whether palmitoylation is required for hippocampal synaptic transmission and fear memory formation, and involved in functional modification of synaptic proteins, such as postsynapse density-95 (PSD-95) and glutamate receptors, and detected if depalmitoylation by specific enzymes has influence on glutamatergic synaptic plasticity. Our results showed that global palmitoylation level, palmitoylation of PSD-95 and glutamate receptors, postsynapse density localization of PSD-95, surface expression of AMPARs, and synaptic strength of cultured hippocampal neurons were all enhanced by TTX pretreatment, and these can be reversed by inhibition of palmitoylation with palmitoyl acyl transferases inhibitors, 2-bromopalmitate and N-(tert-butyl) hydroxylamine hydrochloride. Importantly, we also found that acyl-protein thioesterase 1 (APT1)-mediated depalmitoylation is involved in palmitoylation of PSD-95 and glutamatergic synaptic transmission. Knockdown of APT1, not protein palmitoyl thioesterase 1, with shRNA, or selective inhibition, significantly increased AMPAR-mediated synaptic strength, palmitoylation levels, and synaptic or surface expression of PSD-95 and AMPARs. Results from hippocampal tissues and fear-conditioned rats showed that palmitoylation is required for synaptic strengthening and fear memory formation. These results suggest that palmitoylation and APT1-mediated depalmitoylation have critical effects on the regulation of glutamatergic synaptic plasticity, and it may serve as a potential target for learning and memory-associated disorders.

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Section: Discussionsupporting

confidence: 92%

APT1-Mediated Depalmitoylation Regulates Hippocampal Synaptic Plasticity

et al. 2022

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“…Indeed, for some membrane receptors that are known to be palmitoylated, no evidence was reported until now for a role of palmitoylation on receptor signalization or trafficking. This is the case for instance of α-AR (Kennedy and Limbird, 1993) and NMDAR (Xia et al, 2019).…”

Section: Discussionmentioning

confidence: 96%

How palmitoylation affects trafficking and signaling of membrane receptors

Jansen

Beaumelle

2021

Biology of the Cell

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S-acylation (or palmitoylation) is a reversible post-translational modification (PTM) that modulates protein activity, signalization and trafficking. Palmitoylation was found to significantly impact the activity of various membrane receptors involved in either pathogen entry, such as CCR5 (for HIV) and anthrax toxin receptors, cell proliferation (epidermal growth factor receptor), cardiac function (β-Adrenergic receptor), or synaptic function (AMPA receptor). Palmitoylation of these membrane receptors indeed affects not only their internalization, localization, and activation, but also other PTMs such as phosphorylation. In this review, we discuss recent results showing how palmitoylation differently affects the biology of these membrane receptors.

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“…Namely, the study by Xia et al , used an acute (30 minute) NtBuHA incubation and made physiological recordings of spontaneous postsynaptic events, which are AMPA receptor mediated, whereas we used a chronic treatment paradigm and imaged postsynaptic calcium transients, which involve both calcium permeable AMPA receptors and NMDA receptors [28,29]. These are crucial differences, considering Xia and colleagues noted a reduction in AMPA, but not NMDA receptor palmitoylation following acute NtBuHA treatment [48], while our previous data show that chronic palmitoylation inhibitor treatment can impact NMDA receptor palmitoylation [28]. Furthermore, we studied NtBuHA effects in Cln1 −/− neurons, which demonstrate dysregulation of both glutamate receptor subtypes [28,29].…”

Section: Discussionmentioning

confidence: 99%

“…Here, we demonstrate that chronic supplementation of NtBuHA in the medium of Cln1 -/primary cortical neurons corrected the increased frequency of postsynaptic calcium transients compared to untreated Cln1 -/neurons. Supporting this finding, recent work [48] shows that NtBuHA treatment impacts AMPA receptor transmission in hippocampal slices, although the effect was a reduction in the amplitude, rather than the frequency, of spontaneous postsynaptic events [48]. This discrepancy is reconciled by methodological differences.…”

Section: Potential Mechanisms For Reduction Of Seizure With Ntbuha Tr...mentioning

confidence: 95%

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Reduction of Neuroinflammation and Seizures in a Mouse Model of CLN1 Batten Disease using the Small Molecule Enzyme Mimetic, N-Tert-Butyl Hydroxylamine

Fyke,

Johansson,

Scott

et al. 2024

Preprint

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Infantile neuronal ceroid lipofuscinosis (CLN1 Batten Disease) is a devastating pediatric lysosomal storage disease caused by pathogenic variants in the CLN1 gene, which encodes the depalmitoylation enzyme, palmitoyl-protein thioesterase 1 (PPT1). CLN1 patients present with visual deterioration, psychomotor dysfunction, and recurrent seizures until neurodegeneration results in death, typically before fifteen years of age. Histopathological features of CLN1 include aggregation of lysosomal autofluorescent storage material (AFSM), as well as profound gliosis. The current management of CLN1 is relegated to palliative care. Here, we examine the therapeutic potential of a small molecule PPT1 mimetic, N-tert-butyl hydroxylamine (NtBuHA), in a Cln1-/- mouse model. Treatment with NtBuHA reduced AFSM accumulation both in vitro and in vivo. Importantly, NtBuHA treatment in Cln1-/- mice reduced neuroinflammation, mitigated epileptic episodes, and normalized motor function. Live cell imaging of Cln1-/- primary cortical neurons treated with NtBuHA partially rescued aberrant synaptic calcium dynamics, suggesting a potential mechanism contributing to the therapeutic effects of NtBuHA in vivo. Taken together, our findings provide supporting evidence for NtBuHA as a potential treatment for CLN1 Batten Disease.

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De‐palmitoylation by N‐(tert‐Butyl) hydroxylamine inhibits AMPAR‐mediated synaptic transmission via affecting receptor distribution in postsynaptic densities

Abstract: Our data suggest that the palmitoylation-deficient state initiated by NtBuHA preferentially reduces AMPAR function, which may potentially be used for the treatment of CNS disorders, especially infantile neuronal ceroid lipofuscinosis (Batten disease).

Cited by 9 publications

References 51 publications

APT1-Mediated Depalmitoylation Regulates Hippocampal Synaptic Plasticity

APT1-Mediated Depalmitoylation Regulates Hippocampal Synaptic Plasticity

How palmitoylation affects trafficking and signaling of membrane receptors

Reduction of Neuroinflammation and Seizures in a Mouse Model of CLN1 Batten Disease using the Small Molecule Enzyme Mimetic, N-Tert-Butyl Hydroxylamine

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