Loss Of PSD-95 Research Articles

Cytokine-Induced GAPDH Sulfhydration Affects PSD95 Degradation and Memory

Induction of a proinflammatory cytokine, interleukin-1β (IL-1β) plays a role in memory impairment associated with various neurological disorders and brain injury. Here we show that IL-1β-induced memory impairment in brain is mediated by hydrogen sulfide (H2S) synthesized by cystathionine beta-synthase (CBS). H2S modifies GAPDH essentially via sulfhydration in dendrites, which promotes its binding to the E3 ligase protein, Siah. Then Siah binds to a critical synaptic scaffolding molecule, PSD95, and leads it to degradation via ubiquitination. In CBS heterozygous mice (cbs(+/-)) and primary neurons depleted with either CBS or IL-1R, IL-1β-induced loss of PSD95 was rescued along with a decrease in the level of GAPDH sulfhydration. Moreover, decrease in the loss of PSD95 in cbs(+/-) mice results in improvement of IL-1β-induced cognitive deficits and neurobehavioral outcomes. Thus, our findings reveal a mechanism where GAPDH sulfhydration appears to be a physiologic determinant of cytokine-induced memory impairment in brain.

Phenotypic abnormalities caused by genetic loss of PSD-95 (Dlg4) reveal a potential role for MAGUKs in autism and Williams Syndrome

Phenotypic abnormalities caused by genetic loss of PSD-95 (Dlg4) reveal a potential role for MAGUKs in autism and Williams Syndrome

Ubiquitin and Protein Turnover in Synapse Function

Enduring modification of synapses is central to long-lasting neural circuit plasticity. Such adaptations include rapid posttranslational modification of existing synaptic proteins over periods of minutes and persisting changes in the abundance of synaptic proteins over hours to days. Recently, ubiquitination and protein degradation have emerged as additional mechanisms for modifying the function and molecular composition of synapses. These recent findings raise intriguing questions as to how enduring changes at synapses are accomplished in the face of robust, ongoing molecular turnover.