Differential Role of the Proteasome in the Early and Late Phases of BDNF-Induced Facilitation of LTP

Santos, Ana Rita; Mele, Miranda; Vaz, Sandra H.; Kellermayer, Blanka; Grimaldi, Maddalena; Colino-Oliveira, Mariana; Rombo, Diogo M.; Comprido, Diogo; Sebastião, Ana M.; Duarte, Carlos B.

doi:10.1523/jneurosci.4521-14.2015

Cited by 37 publications

(29 citation statements)

References 57 publications

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“…In contrast, no significant loss of Lin28a was observed over 3 hr in the presence of BDNF (Figure 1E). BDNF and excitatory neuronal activity are generally reported to increase ubiquitin-proteasome-mediated turnover of cellular proteins (Bingol and Schuman, 2006; Ehlers, 2003; Jia et al, 2008; Lin et al, 2011; but see Santos et al, 2015). However, taken together, these results indicate that rapid induction of Lin28a protein levels by BDNF occurs by enhanced Lin28a protein stability.…”

Section: Resultsmentioning

confidence: 99%

A Rapid Induction Mechanism for Lin28a in Trophic Responses

et al. 2017

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SUMMARY Environmental cues provoke rapid transitions in gene expression to support growth and cellular plasticity through incompletely understood mechanisms. Lin28 RNA-binding proteins have evolutionarily conserved roles in post-transcriptional coordination of pro-growth gene expression, but signaling pathways allowing trophic stimuli to induce Lin28 have remained uncharacterized. We find that Lin28a protein exhibits rapid basal turnover in neurons and that mitogen-activated protein kinase (MAPK)-dependent phosphorylation of the RNA-silencing factor HIV TAR-RNA-binding protein (TRBP) promotes binding and stabilization of Lin28a, but not Lin28b, with an accompanying reduction in Lin28-regulated miRNAs, downstream of brain-derived neurotrophic factor (BDNF). Binding of Lin28a to TRBP in vitro is also enhanced by phospho-mimic TRBP. Further, phospho-TRBP recapitulates BDNF-induced neuronal dendritic spine growth in a Lin28a-dependent manner. Finally, we demonstrate MAPK-dependent TRBP and Lin28a induction, with physiological function in growth and survival, downstream of diverse growth factors in multiple primary cell types, supporting a broad role for this pathway in trophic responses.

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Section: Resultsmentioning

confidence: 99%

A Rapid Induction Mechanism for Lin28a in Trophic Responses

et al. 2017

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“…Proteasome activity is essential for the developmental effects of BDNF (Leal et al, 2014;Santos et al, 2015), a protein downregulated in schizophrenia (Jindal et al, 2010;Green et al, 2011;Zhang et al, 2012). Both activation and localization of proteasomes to synapses is essential for regulating synaptic strength and dendritic pruning, and phosphorylation of Rpt6 is necessary for activity-dependent localization of the proteasome to the synapse (Djakovic et al, 2012;Ertürk et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Protein Expression of Proteasome Subunits in Elderly Patients with Schizophrenia

Scott

Rubio

Haroutunian

et al. 2015

Neuropsychopharmacol

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The ubiquitin proteasome system (UPS) is a major regulator of protein processing, trafficking, and degradation. While protein ubiquitination is utilized for many cellular processes, one major function of this system is to target proteins to the proteasome for degradation. In schizophrenia, studies have found UPS transcript abnormalities in both blood and brain, and we have previously reported decreased protein expression of ubiquitin-associated proteins in brain. To test whether the proteasome is similarly dysregulated, we measured the protein expression of proteasome catalytic subunits as well as essential subunits from proteasome regulatory complexes in 14 pair-matched schizophrenia and comparison subjects in superior temporal cortex. We found decreased expression of Rpt1, Rpt3, and Rpt6, subunits of the 19S regulatory particle essential for ubiquitin-dependent degradation by the proteasome. Additionally, the α subunit of the 11S αβ regulatory particle, which enhances proteasomal degradation of small peptides and unfolded proteins, was also decreased. Haloperidol-treated rats did not have altered expression of these subunits, suggesting the changes we observed in schizophrenia are likely not due to chronic antipsychotic treatment. Interestingly, expression of the catalytic subunits of both the standard and immunoproteasome were unchanged, suggesting the abnormalities we observed may be specific to the complexed state of the proteasome. Aging has significant effects on the proteasome, and several subunits (20S β2, Rpn10, Rpn13, 11Sβ, and 11Sγ) were significantly correlated with subject age. These data provide further evidence of dysfunction of the ubiquitin-proteasome system in schizophrenia, and suggest that altered proteasome activity may be associated with the pathophysiology of this illness.

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“…, ), although recent studies also suggested a role for alterations in protein degradation by the proteasome (Santos et al . ).…”

Section: Plasticity Of Gabaergic Synapsesmentioning

confidence: 97%

Role of GABA_AR trafficking in the plasticity of inhibitory synapses

Mele

Leal

Duarte

2016

Journal of Neurochemistry

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Neuronal excitability depends on the balance between inhibitory and excitatory neurotransmission, which in the CNS are mainly mediated by GABA and glutamate respectively. The plasticity of glutamatergic synapses and the underlying molecular mechanisms have been characterized to a large extent. In comparison, much less is known regarding the plasticity of GABAergic synapses, which is also important in the maintenance of the excitatory/inhibitory balance. GABAergic synapses, similarly to the glutamatergic synapses, adjust their strength depending on the pattern of neuronal activity. These alterations take place in the pre-and postsynaptic compartments, and short-and long-term alterations have been described. At the postsynaptic level the plasticity of inhibitory synapses is largely mediated by modulation of the expression, localization and function of GABA A receptors, by mechanisms involving the participation of scaffold proteins and structural molecules. This review is focused on the key mechanisms that regulate GABA A receptor trafficking in response to alterations in neuronal activity or to stimulation of plasma membrane receptors. These alterations in GABAergic neurotransmission are important in the refinement of the pattern of activity of neuronal networks.

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Differential Role of the Proteasome in the Early and Late Phases of BDNF-Induced Facilitation of LTP

Cited by 37 publications

References 57 publications

A Rapid Induction Mechanism for Lin28a in Trophic Responses

A Rapid Induction Mechanism for Lin28a in Trophic Responses

Protein Expression of Proteasome Subunits in Elderly Patients with Schizophrenia

Role of GABA_AR trafficking in the plasticity of inhibitory synapses

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Differential Role of the Proteasome in the Early and Late Phases of BDNF-Induced Facilitation of LTP

Cited by 37 publications

References 57 publications

A Rapid Induction Mechanism for Lin28a in Trophic Responses

A Rapid Induction Mechanism for Lin28a in Trophic Responses

Protein Expression of Proteasome Subunits in Elderly Patients with Schizophrenia

Role of GABAAR trafficking in the plasticity of inhibitory synapses

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Role of GABA_AR trafficking in the plasticity of inhibitory synapses