PSD-95 (SAP90) is a major postsynaptic scaffolding protein of glutamatergic synapses and a substrate of Cdk5. PSD-95 has been implicated in synaptic maturation and regulation of synaptic strength and plasticity. The importance of PSD-95 in synaptic plasticity is underscored by the inhibition of NMDA receptor (NMDAR)-induced AMPA receptor (AMPAR) internalization and the impairment of LTD following PSD-95 knockdown. The rapid and transient ubiquitination of PSD-95 by the Ubiquitin E3 Ligase Mdm2 has been implicated in NMDAR-induced endocytosis of AMPARs, but the mechanisms regulating this posttranslational modification of PSD-95 are still unclear. Since Cdk5 is inactivated by NMDAR stimulation, we investigated whether inactivation of Cdk5 promotes PSD-95 ubiquitination. In this study we report that PSD-95 is ubiquitinated in neurons with reduced Cdk5 activity without affecting PSD-95 protein levels in vivo . We also show that PSD-95 ubiquitination correlates with increased interaction of PSD-95 with β -adaptin, a subunit of the clathrin adaptor protein complex AP-2, and that this interaction is increased under reduced Cdk5 activity or by NMDAR stimulation and is dependent on Mdm2. Together these results suggest a non-proteolytic signaling function for PSD-95 ubiquitination and support a novel function for Cdk5 in the regulation of glutamatergic synapses.
PSD-95 at the crossroads
Crossroads are crucial. The protein PSD-95 stands at a crossroads in the nerve cell synapse of information flowing in both directions between key receptors or channels and signalling systems that connect to cell physiology. This protein is named after a Drosophila homologue - discs large: what better place to study it? It is the most important crossroads protein in the major excitatory synapse of the brain, with the NMDA receptor its best-known interactor. Variation in the level of expression or cellular localisation of PSD-95, and changes to its interaction capacity with partner proteins, play roles in synapse development and plastic changes in learning, but when they go wrong can contribute to neurological and neurodegenerative diseases.
An example from normal development is the movement of PSD-95 from nerve cell soma to synapses in postnatal rodent visual cortical cells after the eyes open (Yoshii et al., 2011). In synaptic plasticity, modulation of PSD-95 ubiquitination controls NMDA receptor induced AMPA receptor endocytosis (Bianchetta et al., 2011).
Genetic evidence points to PSD-95 involvement in schizophrenia: genetic variation in the promoter of the DLG-4 gene associates with schizophrenia (Cheng et al., 2010), and the protein complex including PSD-95 has been convincingly linked to schizophrenia by genomic copy number variant analysis (Kirov et al., 2011).
In Huntington's disease, increases in the well-known excitotoxicity mediated by NMDA receptors may be important. Huntingtin (htt) interacts with PSD-95. In cell culture, pathogenic polyQhtt drives the interaction between PSD-95 and NMDA receptors, leading to increased excitotoxicity (Fan et al., 2009).
PSD-95's lynchpin role in excitotoxicity control is also highlighted by work on Tau toxicity (Ittner et al., 2010). Tau targets Fyn to the synapse, where it phosphorylates PSD-95, increasing PSD-95-NMDAR interaction and excitotoxicity. Its now well accepted that Tau plays an important role in execution of the cell death programme of Alzheimer's disease initiated by AΒ42.
In Alzheimer's disease, falls in PSD-95 level are commonly observed, most notably in mild cognitive impairment, a pre-Alzheimer's state (Sultana et al., 2010), and many studies show effects of AΒ42 on PSD-95 expression. As well as losing function in plasticity and learning, this can also signal increased cell damage via caspase induction (Liu et al., 2010).
PSD-95 is just one of the human proteins which Brainwave-Discovery Ltd. is expressing in Drosophila synapses. We can help you find out the in vivo effects of your compounds on interactions of PSD-95 with its partners, within a normal or an Alzheimer's disease background. We also link in to a Europe-wide synaptic analysis network, SynSys. For more information check out our website or contact firstname.lastname@example.org.
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