Crosstalk between the Rho and Rab family of small GTPases in neurodegenerative disorders

Neurodegeneration is associated with defects in cytoskeletal dynamics and dysfunctions of the vesicular trafficking and sorting systems. In the last few decades, studies have demonstrated that the key regulators of cytoskeletal dynamics are proteins from the Rho family GTPases, meanwhile, the central hub for vesicle sorting and transport between target membranes is the Rab family of GTPases. In this regard, the role of Rho and Rab GTPases in the induction and maintenance of distinct functional and morphological neuronal domains (such as dendrites and axons) has been extensively studied. Several members belonging to these two families of proteins have been associated with many neurodegenerative disorders ranging from dementia to motor neuron degeneration. In this analysis, we attempt to present a brief review of the potential crosstalk between the Rab and Rho family members in neurodegenerative pathologies such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington disease, and amyotrophic lateral sclerosis (ALS)

Behavioral and Transcriptome Profiling of Heterozygous Rab10 Knock-Out Mice

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.A central question in the field of aging research is to identify the cellular and molecular basis of neuroresilience. One potential candidate is the small GTPase, Rab10. Here, we used Rab101/ mice to investigate the molecular mecha-nisms underlying Rab10-mediated neuroresilience. Brain expression analysis of 880 genes involved in neurodegener-ation showed that Rab101/ mice have increased activation of pathways associated with neuronal metabolism, structural integrity, neurotransmission, and neuroplasticity compared with their Rab101/1 littermates. Lower activation was observed for pathways involved in neuroinflammation and aging. We identified and validated several differentially expressed genes (DEGs), including Stx2, Stx1b, Vegfa, and Lrrc25 (downregulated) and Prkaa2, Syt4, and Grin2d (upregulated). Behavioral testing showed that Rab101/ mice perform better in a hippocampal-dependent spatial task (object in place test), while their performance in a classical conditioning task (trace eyeblink classical condition-ing, TECC) was significantly impaired. Therefore, our findings indicate that Rab10 differentially controls the brain cir-cuitry of hippocampal-dependent spatial memory and higher-order behavior that requires intact cortex-hippocampal circuitry. Transcriptome and biochemical characterization of these mice suggest that glutamate ionotropic receptor NMDA type subunit 2D (GRIN2D or GluN2D) is affected by Rab10 signaling. Further work is needed to evaluate whether GRIN2D mediates the behavioral phenotypes of the Rab101/ mice. We conclude that Rab101/ mice de-scribed here can be a valuable tool to study the mechanisms of resilience in Alzheimer’s disease (AD) model mice and to identify novel therapeutical targets to prevent cognitive decline associated with normal and pathologic aging.ECU Open Access Publishing Support Fun

CRY–BARs: Versatile Light-Gated Molecular Tools for the Remodeling of Membrane Architectures

BAR (Bin, Amphiphysin, and Rvs) protein domains are responsible for the generation of membrane curvature and represent a critical mechanical component of cellular functions. Thus, BAR domains have great potential as components of membrane-remodeling tools for cell biologists. In this work, we describe the design and implementation of a family of versatile light-gated I-BAR (inverse BAR) domain containing tools derived from the fusion of the Arabidopsis thaliana cryptochrome 2 photoreceptor and I-BAR protein domains (“CRY–BARs”) with applications in the remodeling of membrane architectures and the control of cellular dynamics. By taking advantage of the intrinsic membrane-binding propensity of the I-BAR domain, CRY–BARs can be used for spatial and temporal control of cellular processes that require induction of membrane protrusions. Using cell lines and primary neuron cultures, we demonstrate here that the CRY–BAR optogenetic tool evokes membrane dynamic changes associated with cellular activity. Moreover, we provide evidence that ezrin, an actin and phosphatidylinositol 4,5-bisphosphate–binding protein, acts as a relay between the plasma membrane and the actin cytoskeleton and therefore is an important mediator of switch function. Overall, we propose that CRY–BARs hold promise as a useful addition to the optogenetic toolkit to study membrane remodeling in live cells