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Cytokine-induced GAPDH sulfhydration affects PSD95 degradation and memory.

Mir S, Sen T, Sen N (2014) Mol Cell.  56(6) 786-95 Elsevier Inc

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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 GAPDHsulfhydration.
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.