Rho-linked genes and neurological disorders

Abstract

Mental retardation (MR) is a common cause of intellectual disability and affects approximately 2 to 3 % of children and young adults. MR has been consistently associated with changes in dendrites and dendritic spine structure. Given that dendritic spine morphology has been tightly linked to synaptic activity, altered spine morphology has been suggested to be the underlying cause of cognitive disabilities observed in MR. The structure and dynamics of dendritic spines is determined by its underlying actin cytoskeleton. Signaling molecules and cascades important for cytoskeletal regulation have therefore naturally attracted a great deal of attention. As key regulators of both the actin and microtubule cytoskeletons, it is not surprising that the Rho GTPases have emerged as important regulators of dendrite and spine structural plasticity. In support of this, mutations in regulators and effectors of Rho GTPases have been associated with diseases affecting the nervous system, including MR and amyotropic lateral sclerosis (ALS). Here we will discuss Rho GTPase related genes and their signaling pathways involved in MR and ALS.

The H3K4me3/2 histone demethylase RBR-2 controls axon guidance by repressing the actin-remodeling gene wsp-1

“…Further, mutations in KDM5B have been reported in individuals with non-syndromic intellectual disability and autism spectrum disorders (Athanasakis et al, 2014;De Rubeis et al, 2014;Iossifov et al, 2014) and mutations in KDM5A have been linked to an autosomal recessive form of intellectual disability (Najmabadi et al, 2011). Similarly, several genes implicated in cytoskeleton dynamics are mutated in intellectual disability and autism spectrum disorders (Nadif Kasri and Van Aelst, 2008;Ba et al, 2013;Hu et al, 2014;Srivastava and Schwartz, 2014). Thus, our results help to establish a functional link between chromatin regulators and the actin-remodeling genes required for axon/dendrite formation and synaptic plasticity, which are processes compromised in neurodevelopmental and psychiatric disorders.…”

The Atypical Guanine Nucleotide Exchange Factor Dock4 Regulates Neurite Differentiation through Modulation of Rac1 GTPase and Actin Dynamics

“…Mutations of Rho GTPases, their regulators, and their downstream signaling molecules have been found in various neurological diseases (2).…”

Cell Type-specific Signaling Function of RhoA GTPase: Lessons from Mouse Gene Targeting

“…In addition, the mouse genetic studies may reveal information about the possible involvement of RhoA signaling in human diseases, and RhoA and its regulator/effector knock-out mice will be useful for evaluating the contribution of RhoA signaling in pathophysiology. To this end, abnormal RhoA signaling has been associated with human cancer, neuronal disorders, and asthma (20,79,80), and the rational design and targeting of the RhoA signaling pathway (81-84) may bear therapeutic value.…”