Comprehensive Analysis of Age- and Sex-Related Expression of the Chaperone Protein Sigma-1R in the Mouse Brain.

Sigma-1R (S1R) is a ubiquitously distributed protein highly expressed in the brain and liver. It acts as a ligand-inducible chaperone protein localized at the endoplasmic reticulum. S1R participates in several signaling pathways that oversee diverse cellular and neurological functions, such as calcium and proteome homeostasis, neuronal activity, memory, and emotional regulation.

Overview of Sigma-1R Subcellular Specific Biological Functions and Role in Neuroprotection.

For the past several years, fundamental research on Sigma-1R (S1R) protein has unveiled its necessity for maintaining proper cellular homeostasis through modulation of calcium and lipid exchange between the endoplasmic reticulum (ER) and mitochondria, ER-stress response, and many other mechanisms. Most of these processes, such as ER-stress response and autophagy, have been associated with neuroprotective roles. In fact, improving these mechanisms using S1R agonists was beneficial in several brain disorders including neurodegenerative diseases.

Autophagy protein NRBF2 has reduced expression in Alzheimer's brains and modulates memory and amyloid-beta homeostasis in mice.

Background: Dysfunctional autophagy is implicated in Alzheimer's Disease (AD) pathogenesis. The alterations in the expression of many autophagy related genes (ATGs) have been reported in AD brains; however, the disparity of the changes confounds the role of autophagy in AD.

Methods: To further understand the autophagy alteration in AD brains, we analyzed transcriptomic (RNAseq) datasets of several brain regions (BA10, BA22, BA36 and BA44 in 223 patients compared to 59 healthy controls) and measured the expression of 130 ATGs.

Autophagy Receptors and Neurodegenerative Diseases.

Previously thought of as a nonselective digestion process, autophagy is now known to specifically degrade aggregated proteins and damaged cellular organelles through the action of autophagy receptors, which provides cellular quality control and maintains homeostasis. Autophagy receptors recognize and recruit specific cargoes to the autophagosome-lysosome pathway for degradation in ubiquitin-dependent and -independent manners, and their functions (in selective autophagy) are regulated by protein modifications, for example, phosphorylation and ubiquitination. Growing evidence has linked the genetic variants of autophagy receptors to neurodegenerative diseases and multiple experimental systems have validated their roles in modulating the disease process.

ULK1-mediated phosphorylation of ATG14 promotes autophagy and is impaired in Huntington's disease models.

Background: Autophagy is a bulk degradation pathway for long-lived proteins, protein aggregates, and damaged organelles. ULK1 protein kinase and Vps34 lipid kinase are two key autophagy regulators that are critical for autophagosome biogenesis. However, it isn't fully understood how ULK1 regulates Vps34, especially in the context of disease.

A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects.

Genetic leukoencephalopathies (gLEs) are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS). The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES), we identified homozygosity for a missense variant, VPS11: c.

New insights in the regulation of Rab GTPases by G protein-coupled receptors.

Cargo-mediated regulation of vesicular transport has received great attention lately. Rab GTPases, forming the largest branch of the Ras GTPase superfamily, regulate almost every step of vesicle-mediated trafficking. Growing evidence suggests that mutations, aberrant expression, and altered post-translational modifications of Rab GTPases are associated with human diseases.

Ubiquitylation and activation of a Rab GTPase is promoted by a β₂AR-HACE1 complex.

We and others have shown that trafficking of G-protein-coupled receptors is regulated by Rab GTPases. Cargo-mediated regulation of vesicular transport has received great attention lately. Rab GTPases, which form the largest branch of the Ras GTPase superfamily, regulate almost every step of vesicle-mediated trafficking.

Regulation of β2-adrenergic receptor maturation and anterograde trafficking by an interaction with Rab geranylgeranyltransferase: modulation of Rab geranylgeranylation by the receptor.

Previous reports by us and others demonstrated that G protein-coupled receptors interact functionally with Rab GTPases. Here, we show that the β(2)-adrenergic receptor (β(2)AR) interacts with the Rab geranylgeranyltransferase α-subunit (RGGTA). Confocal microscopy showed that β(2)AR co-localizes with RGGTA in intracellular compartments and at the plasma membrane.

Rack1 is required for Vangl2 membrane localization and planar cell polarity signaling while attenuating canonical Wnt activity.

The vertebrate planar cell polarity (PCP) pathway shares molecular components with the β-catenin-mediated canonical Wnt pathway but acts through membrane complexes containing Vang or Frizzled to orient neighboring cells coordinately. The molecular interactions underlying the action of Vang in PCP signaling and specification, however, are yet to be delineated. Here, we report the identification of Rack1 as an interacting protein of a vertebrate Vang protein, Vangl2.