JNK3 as a Therapeutic Target for Neurodegenerative Diseases

Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 02/2011; 24(4):633-42. DOI: 10.3233/JAD-2011-091567
Source: PubMed


c-Jun N-terminal kinases (JNKs) and in particular JNK3 the neuronal specific isoform, have been recognized as important enzymes in the pathology of diverse neurological disorders. Indeed, several efforts have been made to design drugs that inhibit JNK signaling. The success that characterized the new generation of cell permeable peptides raise the hope in the field of neurodegeneration for new therapeutic routes. However, in order to design new and more efficient therapeutical approaches careful re-examination of current knowledge is required. Scaffold proteins are key endogenous regulators of JNK signaling: they can modulate spatial and temporal activation of the JNK signaling and can thus provide the basis for the design of more specific inhibitors. This review focuses on delineating the role of scaffold proteins on the regulation of JNK signaling in neurons. Furthermore the possibility to design a new JNK3 cell permeable peptide inhibitor by targeting the β-arrestin-JNK3 interaction is discussed.

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    • "Thus, much attention has been paid to the design of new inhibitors of this kinase family for the treatment of malignant disorders (Pratilas and Solit, 2010; Santarpia et al., 2012). JNK3 is predominantly expressed in the brain, testes, and heart (Bode and Dong, 2007), and its specific inhibition is able to inhibit neurodegenerative diseases in animal models (Parkinson and Alzheimer diseases) (Antoniou et al., 2011). JNK1 and JNK2 are ubiquitously expressed in tissues and can present with similar or different functions (Davis, 2000). "
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    ABSTRACT: The c-Jun N-terminal kinase (JNK) family, with its three members JNK1, JNK2, and JNK3, is a subfamily of mitogen-activated protein kinases. Involved in many aspects of cellular processes, JNK has been also associated with pathological states such as neurodegenerative diseases, inflammation, and cancers. In oncology, each isoform plays a distinct role depending on the context of the targeted tissue/organ, the tumor stage, and, most likely, the signaling pathway activated upstream. Consequently, the current challenge in finding new successful anti-JNK therapies is to design isoform-selective inhibitors of the JNKs. In this review, a particular focus is given to the JNK inhibitors that have been developed thus far when examining 3D structures of various JNK-inhibitor complexes. Using current data regarding structure-activity relationships and medicinal chemistry approaches, our objective is to provide a better understanding of the design and development of selective JNK inhibitors in the present and future. Copyright © 2014 Elsevier Ltd. All rights reserved.
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    • "By increasing our knowledge of how each of the substrates interacts with STEP, we may be able to develop substrate-interfering peptides. This strategy is currently being employed to develop cell penetrating c-Jun N-terminal kinase inhibitors to block the interaction of c-Jun N-terminal kinase with its scaffolding partners in the treatment of neurodegenerative diseases (Antoniou et al., 2011). Alternatively, cell-permeable peptides that mimic endogenous inhibitors of STEP may provide a degree of isoform specificity. "
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    • "c-Jun is a basic region leucine-zipper transcription factor that forms homo-and heterodimers, latter in combination with c-fos, ATF, CREB, steroid hormone receptor, or JDP members. It binds to the AP-1, CRE, or NF-AT consensus sequence in promoter regions of immediate early genes (see review: Antoniou et al., 2011). The transcription factor is not only essential to neuronal differentiation but is also a powerful mediator of neuronal apoptotic signal cascades involving c-Jun N-terminal kinases (JNKs, Kyriakis et al., 1994). "
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