Proteasome-Mediated Degradation of RISC: Lead Target for Treatment of Long-Term Memory Disorders

Summary Background: Breakthrough research by Professor Sam Kunes and colleagues at Harvard University demonstrates that degradative control of the miRNA RISC pathway underlies the synaptic pattern of protein synthesis associated with the establishment of a stable long-memory. Manipulation of this pathway has implications not only for long-term memory, but also additional neurological disorders such as Parkinson’s and Huntington’s disease. This pathway includes several proteins that can be important targets for pharmacological intervention, including the SDE3 helicase Armitage. This technology also provides an excellent complement to their existing neurological drug pipeline. Harvard is seeking a long-term partnership with for the development of this exciting technology.

Invention: CaMKII-Deficienta Animals display a near complete loss of LTM. The Drosophila CaMKII protein is involved in neuromuscular synaptic plasticity and memory in the courtship-conditioning paradigm. It is localized to puncta on Projection Neuron dendrites and at the pre-synaptic boutons of Projection Neuron axonal branches in the mushroom body calyx and lateral horn. By using a “spaced training” model (see above) for establishment of long-term memory, the inventors have been able to monitor, for the first time, the mRNA of the Drosophila Ca2+, Calmodulin-dependent protein kinase II (CaMKII) to post-synaptic sites, where it is translated. These features of CaMKII expression are recapitulated during the induction of a long-term memory, and produce a pattern of local protein synthesis specific to the memory. More importantly, animals targeted for loss of CaMKII expression displayed severe long-term memory problems.

Applications The RISC MicroRNA Pathway Regulates the Synaptic Synthesis of CAMKII and the Establishment of Long Term Memory: The RISC complex is the protein RNA complex that underlies RNA interference. An examination of the amino sequence of CaMKII reveals a miRNA binding site in the CaMKII 3”UTR. Overexpression of the RNA helicase Armitage, a component of the RISC complex, reduces the amount of CaMKII; while a mutant CaMKII in the 3’ UTR increases the amount of CaMKII. Moreover, cell lines null for Armitage displayed increased expression of CaMKII. In either the armi/armi or armi/+ genetic backgrounds, the expression of CaMKII is reduced in neurons that strongly express Armitage. In contrast, a high-level of CaMKII is observed in armi/armi neurons that express Armitage weakly. Most importantly, these flies had twice the memory of their normal counterparts.

Proteasome-Mediated Degradation of Armitage Potentiates Long-Term Memory Formation: In the presence of nicotine, the level of level of Armitage decreased 3.5 fold, while there was a correlated 4.5 increase in CaMKII expression in the same neurons. Prior incubation with the proteasome inhibitor lactacystin blocked the nicotine-induced loss of Armi expression and downregulated the expression of CaMKII. RT-PCR analysis comparing wild type and Armi mutant adult brains did not detect a difference in the level of transgenic mRNA’s, thus indicating regulation at the post-transcriptional level. For Further Information Please Contact the Director of Business Development Laura Brass Email: laura_brass@harvard.edu Telephone: (617) 495-3067

Inventor(s): Kunes, Sam

Type of Offer: Licensing



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