LIM-Kinases in Synaptic Plasticity, Memory, and Brain Diseases

Abstract

Learning and memory require structural and functional modifications of synaptic connections, and synaptic deficits are believed to underlie many brain disorders. The LIM-domain-containing protein kinases (LIMK1 and LIMK2) are key regulators of the actin cytoskeleton by affecting the actin-binding protein, cofilin. In addition, LIMK1 is implicated in the regulation of gene expression by interacting with the cAMP-response element-binding protein. Accumulating evidence indicates that LIMKs are critically involved in brain function and dysfunction. In this paper, we will review studies on the roles and underlying mechanisms of LIMKs in the regulation of long-term potentiation (LTP) and depression (LTD), the most extensively studied forms of long-lasting synaptic plasticity widely regarded as cellular mechanisms underlying learning and memory. We will also discuss the involvement of LIMKs in the regulation of the dendritic spine, the structural basis of synaptic plasticity, and memory formation. Finally, we will discuss recent progress on investigations of LIMKs in neurological and mental disorders, including Alzheimer’s, Parkinson’s, Williams–Beuren syndrome, schizophrenia, and autism spectrum disorders.

Structural Aspects of LIMK Regulation and Pharmacology

“…Dephosphorylation by Slingshot homolog 1 (SSH1) restores ADF activity [ 4 ]. Like this, the LIMKs and SSH1 control the dynamics of the actin cytoskeleton, with significant roles in physiology and disease [ 5 ]. There are two LIMKs expressed in humans, namely LIMK1 and LIMK2, both containing a kinase domain in their C terminus ( Figure 1 B).…”

The Role of LIM Kinases during Development: A Lens to Get a Glimpse of Their Implication in Pathologies

“…The increasing number of publications describing a role for LIMKs at almost all stages of development and in adults suggests an important role of LIMKs also in pathological situations. Indeed there are numerous reviews that report deregulation of the cofilin pathway, including LIMK activity/expression in neurological and mental disorders [25,29,123], in cancer and metastasis [28,124], and in several urogenital diseases such as erectile dysfunction and infertility [125].…”

“…This rare genetic disorder, first described by New Zealand's Dr. John Cyprian Phipps Williams in 1961 and in the following year by Germany's Dr. Alois J. Beuren, is caused by the hemizygous deletion of approximately 1.5-1.8 mega base pairs on the long arm of chromosome 7 (7q11.23), encompassing 27 genes including elastin, CLIP115 and LIMK1. Some of the clinical characteristics of Williams-Beuren syndrome [23], such as distinctive craniofacial abnormalities (broad forehead, wide mouth, full cheeks and lips, and oval ears), impaired visuospatial constructive cognition, and mild mental retardation have been specifically associated with the deletion of LIMK1 [24][25][26].…”

“…Understanding the role of LIMKs during development may indeed shed light on the LIMK-dependent pathological perturbations observed not only in Williams-Beuren syndrome but also in other pathologies (autism, fragile X syndrome (see the recent review of Ben Zablah and collaborators [25]) or carcinogenesis (see reviews of Lee and collaborators [27] or of Fabrizio Manetti [28,29])).…”

LIM Kinases, Promising but Reluctant Therapeutic Targets: Chemistry and Preclinical Validation In Vivo

“…By regulating cytoskeleton dynamics [2,3], LIMKs are involved in numerous cellular functions, such as cell motility, morphogenesis, division, differentiation, apoptosis, neuronal morphology, and neuritogenesis. As a result, they are implicated in multiple pathologies: oncogenesis, by controlling tumor progression and metastasis development [4]; the resistance of cancers to chemotherapy targeting microtubules (MT) [5,6]; viral infections [7,8], ocular diseases (glaucoma) [9]; pain [10]; erectile dysfunction [11,12]; neurofibromatosis types 1 and 2 [13][14][15]; and neuronal diseases [16,17].…”