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Palmitoyl-proteins : regulators of neuronal functions and potential targets for neuroprotection

University of British Columbia

Protein palmitoylation is an important post-translational lipid modification. While hundreds of palmitoyl proteins have been identified in neurons, little is known about how palmitoylation regulates these neuronal proteins and how it contributes to neuronal development and function. A special group of palmitoyl proteins, 23 mammalian zinc-finger DHHC-type containing (zD) proteins are potent palmitoyl acyltransferases (PATs) that catalyze protein palmitoylation. However, the physiopathological roles of these PATs in brain function are largely elusive. AMPA receptor (AMPAR) subunit GluR1 and GluR2 are palmitoyl proteins. In this thesis, I have found that GluR1 and GluR2 show different palmitoylation properties in neurons. Palmitoylation regulate AMPAR stability in a subunit-selective manner in response to synaptic stimulations. In addition, c-jun N-terminal kinase 3 (JNK3), but not other JNK isoforms, has been identified in this thesis as a novel palmitoyl protein. Without palmitoylation, JNK3 is associated more strongly with the cytoskeleton and promotes axonal branching. This suggests a potential role of palmitoylation in modulating axonal development via isoform-specific regulation of JNK3. I have further revealed that zD17 mediates neuronal responses in acute ischemic brain injury via a mechanism independent of its PAT activity. ZD17 directly interacts with JNK to form a signaling module for JNK activation. Pathological stressors induce the zD17-JNK interaction which promotes downstream neuronal cell death signals. I have developed novel peptides targeting the JNK-interacting motif on zD17 to selectively block the enhancement of the zD17-JNK interaction and the activation of JNK isoforms 2 and 3. Application of these peptides successfully blocks JNK activation and neuronal cell death pathways, protects cultured neurons from excitotoxicity, and dramatically reduces brain damage and behavioural deficits in a rat model of focal ischemic stroke. These findings indicate PAT zD17 as a key player in ischemic stroke, and suggest the potential therapeutic value of targeting palmitoyl proteins for neuroprotection.

Text

2011-10-21

Attribution-NonCommercial-NoDerivs 3.0 Unported

http://hdl.handle.net/2429/38155

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/3.0/