Abstract
The synaptic regulator, kalirin, plays a key role in synaptic plasticity and formation of dendritic arbors and spines. Dysregulation of the KALRN gene has been linked to various neurological disorders, including autism spectrum disorder, Alzheimer's disease, schizophrenia, addiction and intellectual disabilities. Both genetic and molecular studies highlight the importance of normal KALRN expression for healthy neurodevelopment and function. This review aims to give an in-depth analysis of the structure and molecular mechanisms of kalirin function, particularly within the brain. These data are correlated to genetic evidence of patient mutations within KALRN and animal models of Kalrn that together give insight into the manner in which this gene may be involved in neurodevelopment and the etiology of disease. The emerging links to human disease from post-mortem, genome wide association (GWAS) and exome sequencing studies are examined to highlight the disease relevance of kalirin, particularly in neurodevelopmental diseases. Finally, we will discuss efforts to pharmacologically regulate kalirin protein activity and the implications of such endeavors for the treatment of human disease. As multiple disease states arise from deregulated synapse formation and altered KALRN expression and function, therapeutics may be developed to provide control over KALRN activity and thus synapse dysregulation. As such, a detailed understanding of how kalirin regulates neuronal development, and the manner in which kalirin dysfunction promotes neurological disease, may support KALRN as a valuable therapeutic avenue for future pharmacological intervention.
Original language | English (US) |
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Article number | 145306 |
Journal | Gene |
Volume | 768 |
DOIs | |
State | Published - Feb 5 2021 |
Funding
This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from https://decipher.sanger.ac.uk and via email from [email protected]. Funding for the project was provided by Wellcome. This review and the corresponding Gene Wiki article are written as part of the Gene Wiki Review series--a series resulting from a collaboration between the journal GENE and the Gene Wiki Initiative. The Gene Wiki Initiative is supported by National Institutes of Health (GM089820). Additional support for Gene Wiki Reviews is provided by Elsevier, the publisher of GENE. This work was funded by the NIMH grant R01MH071316. This review and the corresponding Gene Wiki article are written as part of the Gene Wiki Review series?a series resulting from a collaboration between the journal GENE and the Gene Wiki Initiative. The Gene Wiki Initiative is supported by National Institutes of Health (GM089820). Additional support for Gene Wiki Reviews is provided by Elsevier, the publisher of GENE. This work was funded by the NIMH grant R01MH071316. This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from https://decipher.sanger.ac.uk and via email from [email protected]. Funding for the project was provided by Wellcome. The corresponding Gene Wiki entry for this review can be found here en.wikipedia.org/wiki/Kalirin. Manuscript concept and design: EP. Figure generation: EP and LS. Drafting of the manuscript: EP, LS and RV. Critical revision of the manuscript for intellectual content: EP, LS, RV, MF, DL, HJ. Obtained funding and supervised: PP.
Keywords
- Alzheimer's disease
- Autism spectrum disorder
- Dendritic spine
- Developmental delay
- KALRN
- Kalirin
- Neurodegeneration
- Neurodevelopment
- Schizophrenia
- Synaptic plasticity
ASJC Scopus subject areas
- Genetics