Considerable evidence suggests that synaptic function is severely compromised in Alzheimer's disease and other neurodegenerative diseases, leading to cognitive defects even during the early stages of these diseases. It is well known that protein phosphatase-1 (PP1) plays a critical role in synaptic function. However, our preliminary data indicates that there are at least two synaptic PP1 populations which can exert differential functions on synaptic transmission. Our immediate goal is to elucidate the differential targeting and signaling mechanisms underlying these two synaptic PP1 populations. Our longer-term goal is to apply this knowledge in understanding how impairment of PP1 signaling in synaptic function can be prevented in diseases. Our newly acquired preliminary data suggest that two distinct pools of PP1, probably targeted respectively by neurabin and spinophilin, have opposite functions in synaptic transmission and play differential roles in long term depression (LTD). In this proposal, we hypothesize that neurabin and spinophilin can exert their opposite effects on basal synaptic transmission (Aim 1) through micro-targeting their cargoes (PP1) to distinct micro-compartments within synapses, acting on different substrates, i.e, Ser657 on PKC? (and indirectly on Ser880 on GluR2) and Ser831 on GluR1, respectively. In response to LTD stimulus (Aim2), we propose to test our hypothesis that neurabin will traffic to PSD fraction to dephosphorylate GSK3?, leading to synaptic depression while spinophilin does not play a role in this process. Critical domains on neurabin and spinophilin mediating their distinct effects will be elucidated in these two aims by a combination of electrophysiological recording and the state-of-the-art molecular replacement approach.
In Aim3, we will hypothesize that neurabin, but not spinophilin, plays a negative role in LTP expression. We propose to determine the phosphorylation mechanism on neurabin by which LTP stimulus uses to overcome the inhibitory effects of Nrb/PP1 complex for normal LTP to occur. Finally we will also test the hypotheses that Nrb/PP1 modifies CaMKII and/or GSK3? for its inhibitory function in LTP. The results obtained from these studies will provide a better understanding of biological mechanisms that (1) regulate PP1 interaction with different binding proteins for differential substrate specificity, (2) structural basis for the critical functions of neurabin and spinophilin in synaptic functions;and (3) provide insights into therapeutic cures for the cognitive defects in patients with neuro-degenerative diseases.

Public Health Relevance

Considerable evidence suggests that synaptic function is severely compromised in Alzheimer's disease and other neurodegenerative diseases, leading to cognitive defects even during the early stages of these diseases. Our proposed study is to examine the phosphatases signaling mechanisms underlying synaptic functions. The results obtained from these studies will provide molecular insights into therapeutic cures for the cognitive defects in patients with neuro-degenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS060879-04
Application #
8231537
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Talley, Edmund M
Project Start
2009-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
4
Fiscal Year
2012
Total Cost
$304,413
Indirect Cost
$90,038
Name
Louisiana State Univ Hsc New Orleans
Department
Neurosciences
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
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Siddoway, Benjamin A; Altimimi, Haider F; Hou, Hailong et al. (2013) An essential role for inhibitor-2 regulation of protein phosphatase-1 in synaptic scaling. J Neurosci 33:11206-11
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