CaMKK2 as an emerging treatment target for bipolar disorder.

Autor: Kaiser J; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia.; St Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia.; School of Behavioural and Health Sciences, Australian Catholic University, Fitzroy, VIC, 3065, Australia., Nay K; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia., Horne CR; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia., McAloon LM; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia.; St Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia.; School of Behavioural and Health Sciences, Australian Catholic University, Fitzroy, VIC, 3065, Australia., Fuller OK; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia., Muller AG; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia.; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia., Whyte DG; School of Behavioural and Health Sciences, Australian Catholic University, Fitzroy, VIC, 3065, Australia., Means AR; Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA., Walder K; The Institute for Mental and Physical Health and Clinical Translation (IMPACT), School of Medicine, Deakin University, Geelong, VIC, 3220, Australia., Berk M; The Institute for Mental and Physical Health and Clinical Translation (IMPACT), School of Medicine, Deakin University, Geelong, VIC, 3220, Australia.; Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, VIC, 3052, Australia.; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia., Hannan AJ; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia.; Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3052, Australia., Murphy JM; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia.; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia., Febbraio MA; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia., Gundlach AL; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia.; St Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia.; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia.; Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3052, Australia., Scott JW; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia. John.Scott@monash.edu.; St Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia. John.Scott@monash.edu.; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia. John.Scott@monash.edu.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2023 Nov; Vol. 28 (11), pp. 4500-4511. Date of Electronic Publication: 2023 Sep 20.
DOI: 10.1038/s41380-023-02260-3
Abstrakt: Current pharmacological treatments for bipolar disorder are inadequate and based on serendipitously discovered drugs often with limited efficacy, burdensome side-effects, and unclear mechanisms of action. Advances in drug development for the treatment of bipolar disorder remain incremental and have come largely from repurposing drugs used for other psychiatric conditions, a strategy that has failed to find truly revolutionary therapies, as it does not target the mood instability that characterises the condition. The lack of therapeutic innovation in the bipolar disorder field is largely due to a poor understanding of the underlying disease mechanisms and the consequent absence of validated drug targets. A compelling new treatment target is the Ca 2+ -calmodulin dependent protein kinase kinase-2 (CaMKK2) enzyme. CaMKK2 is highly enriched in brain neurons and regulates energy metabolism and neuronal processes that underpin higher order functions such as long-term memory, mood, and other affective functions. Loss-of-function polymorphisms and a rare missense mutation in human CAMKK2 are associated with bipolar disorder, and genetic deletion of Camkk2 in mice causes bipolar-like behaviours similar to those in patients. Furthermore, these behaviours are ameliorated by lithium, which increases CaMKK2 activity. In this review, we discuss multiple convergent lines of evidence that support targeting of CaMKK2 as a new treatment strategy for bipolar disorder.
(© 2023. The Author(s).)
Databáze: MEDLINE
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