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Abelson Kinase Family in Regulation of Synpatic Activity and Plasticity

Abelson (Abl) non-receptor tyrosine kinases act in the cytoplasm to coordinate remodeling of actin microfilaments in response to appropriate stimuli. The Abl kinase family contains Abl-1 and Abl-2 (Arg- Abl related gene) proteins, which play multiple roles in the CNS, including neurulation and neurite outgrowth. Abl was shown to localize in the synaptic compartment on both sides of the synaptic cleft, at presynapses and dendrite spines, being particularly prominent at post-synaptic densities (PSD).

In the hippocampus, Abl-1 modulates neurotransmitter release at Schaffer collateral–CA1 synapses, inhibits NMDA receptors downstream to the PDGFb receptor and co-localizes with PSD95, regulating its clustering by tyrosine phosphorylation. Abl kinases modulate short-term synaptic plasticity, while Rin1, an upstream regulator of Abl-1, affects long-term synaptic plasticity and impairs conditioned fear extinction. Moreover, Rin1-null mice showed normal long-term depression, but enhanced depotentiation, which was impaired by introduction of an Abl kinase inhibitor. Loss of Abl-interactor (Abi), involved in Abl kinase signaling, leads to abnormal dendritic spine morphology and density, as well as a severe deficit in short- and long-term memory. Furthermore, Abl was shown to be involved in the pathogenesis of Alzheimer's disease (AD): subcellular distribution of Abl kinases in the hippocampus was shown to be altered in AD patients, while amyloid Ab-peptide and reactive oxygen species were both shown to activate Abl kinase. Moreover, the Abl kinase inhibitor, STI571 (Imatinib), prevents Abl/p73 signaling pathway- related apoptosis, microtubule associated Tau protein hyper-phosphorylation and was found to decrease the production of amyloid species by inhibiting gamma-cleavage of the amyloid precursor protein's C-terminal fragment (APP-CTF).

In our Laboratory

We conduct research of involvement of Abl kinase family proteins in regulation of synaptic activity and plasticity.

 
Findings
Abl Kinases Mediate the Effect of Monomeric Amyloid Beta Peptides on Presynaptic Release

In cultured hippocampal neurons pharmacological inhibition of Abl kinases (by imatinib and bafetinib) and knockdown using specific siRNA directed to Abl1 and Abl2 led to enhancement of spontaneous presynaptic activity increasing frequency of mEPSCs (miniature excitatory post-synaptic current), while pharmacological activation of Abl kinases by DPH led to opposite effect up to complete elimination of mEPSCs.  The activation of Abl1 by monomeric amyloid beta (Aβ1-42) peptides at low nanomolar concentration also showed the reduction of spontaneous synaptic release, while this effect can be reversed by inhibition of Abl kinase activity (pharmacologically) or expression (knockdown Abl1 and Abl2 specific siRNAs). The electrophysiological data were further strongly supported by biochemical analysis showing enhanced phosphorylation of Abl kinase substrate (Crkl) upon treatment of cultured hippocampal neurons with Aβ peptides. We conclude that Abl signaling may mediate the Aβ-induced weakening of synaptic transmission.

Abl Kinases are Involved In Regulation of Long-Term Synaptic Plasticity and Long-Term Spatial Memory Formation

Proteomic study of spatial reference memory formation using eight arm radial maze paradigm revealed dramatic changes in Abl2 (Arg) kinase and Abl-interacting protein 2 (Abi-2) during over the time course of learning. Moreover, our preliminary findings revealed strong enhancing effect of Abl kinases activation on late-phase long-term potentiation in freely moving animals. Surprisingly, these findings are in controversy with other our preliminary results, which demonstrate that Abl activation with DPH reduced mEPSC amplitudes. Abl activation led to reduction of both AMPA and NMDA receptors current.

Plans

We focus on two major directions: 1) investigation of the role of Abl kinases in mediation of Amyloid beta peptides effect on the presynaptic activity; 2) investigation of the role of Abl kinases in regulation of late phase LTP and reference memory. For these reason, we investigate upstream signaling cascades leading to Abl activation by Aβ peptides, as well as we try to delineate which proteins may be downstream effectors of Abl kinases in mediation of reduction of presynaptic spontaneous release. In addition, we are interested whether Abl kinases are involved in the effects of oligomeric and fibrillary forms of Aβ peptides on the presynaptic release both spontaneous and evoked ones. Regarding the effect of Abl kinases on long-term synaptic plasticity and memory, we investigate how Abl kinase activity affects long-term memory and at which its phase is the effect of Abl kinases the most crucial. In addition, we study by which mechanism Abl kinases may enhance synaptic plasticity despite their depressing effect on post-synaptic activity on the short term of regulation.

This study is interdisciplinary encompassing several methodological approaches from electrophysiology to behavioral paradigms, from proteomics to biochemical and immunohistochemical methods of study.

Projects
  1. Identification and study of physiological and pathological roles of the signaling cascade leading to Abl kinase activation downstream from Aβ peptides  (Ph.D or Post-Doctoral position, B001)

  2. Investigation of the mechanism by which Abl kinase affects presynaptic release (Ph.D or Post-Doctoral position, B002)

  3. Elucidation of the mechanism by which Abl kinase affects late phase long-term synaptic plasticity and long-term memory (Ph.D or Post-Doctoral position, B003)

Related References from our Lab
  • Reichenstein M, Sheinin A, Borovok N, Michaelevski I. Abl Kinase mediates spontaneous synaptic activity depression induced by Amyloid Beta 1-42 peptides (Pending on revision, Neurobiology of Aging)

  • Reichenstein M, Sheinin A, Borovok N, Michaelevski I Abl2 kinase effect on post-synaptic neuronal activity is mediated by regulation of AMPA receptor current. (in preparation).

Plans
Our Findings
References
Projects
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