Interplay between and mutations governs innate immune responses in diffuse gliomas.

Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in , defining molecular alterations in -mutant astrocytomas, have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss and mutation on innate immunity.

Ankyrin-B metabolic syndrome combines age-dependent adiposity with pancreatic β cell insufficiency.

Rare functional variants of ankyrin-B have been implicated in human disease, including hereditary cardiac arrhythmia and type 2 diabetes (T2D). Here, we developed murine models to evaluate the metabolic consequences of these alterations in vivo. Specifically, we generated knockin mice that express either the human ankyrin-B variant R1788W, which is present in 0.

A PIK3C3-ankyrin-B-dynactin pathway promotes axonal growth and multiorganelle transport.

Axon growth requires long-range transport of organelles, but how these cargoes recruit their motors and how their traffic is regulated are not fully resolved. In this paper, we identify a new pathway based on the class III PI3-kinase (PIK3C3), ankyrin-B (AnkB), and dynactin, which promotes fast axonal transport of synaptic vesicles, mitochondria, endosomes, and lysosomes. We show that dynactin associates with cargo through AnkB interactions with both the dynactin subunit p62 and phosphatidylinositol 3-phosphate (PtdIns(3)P) lipids generated by PIK3C3.

E-cadherin polarity is determined by a multifunction motif mediating lateral membrane retention through ankyrin-G and apical-lateral transcytosis through clathrin.

We report a highly conserved motif in the E-cadherin juxtamembrane domain that determines apical-lateral polarity by conferring both restricted mobility at the lateral membrane and transcytosis of apically mis-sorted protein to the lateral membrane. Mutations causing either increased lateral membrane mobility or loss of apical-lateral transcytosis result in partial mis-sorting of E-cadherin in Madin-Darby canine kidney cells. However, loss of both activities results in complete loss of polarity.

Ankyrin-B interactions with spectrin and dynactin-4 are required for dystrophin-based protection of skeletal muscle from exercise injury.

Costameres are cellular sites of mechanotransduction in heart and skeletal muscle where dystrophin and its membrane-spanning partner dystroglycan distribute intracellular contractile forces into the surrounding extracellular matrix. Resolution of a functional costamere interactome is still limited but likely to be critical for understanding forms of muscular dystrophy and cardiomyopathy. Dystrophin binds a set of membrane-associated proteins (the dystrophin-glycoprotein complex) as well as γ-actin and microtubules and also is required to align sarcolemmal microtubules with costameres.

Oligodendrocytes and progenitors become progressively depleted within chronically demyelinated lesions.

To understand mechanisms that may underlie the progression of a demyelinated lesion to a chronic state, we have used the cuprizone model of chronic demyelination. In this study, we investigated the fate of oligodendrocytes during the progression of a demyelinating lesion to a chronic state and determined whether transplanted adult oligodendrocyte progenitors could remyelinate the chronically demyelinated axons. Although there is rapid regeneration of the oligodendrocyte population following an acute lesion, most of these newly regenerated cells undergo apoptosis if mice remain on a cuprizone diet.

Normal metabolism but different physical properties of myelin from mice deficient in proteolipid protein.

Proteolipid protein (PLP) is the primary protein component of CNS myelin, yet myelin from the PLP(null) mouse has only minor ultrastructural abnormalities. Might compensation for a potentially unstable structure involve increased myelin synthesis and turnover? This was not the case; neither accumulation nor in vivo synthesis rates for the myelin-specific lipid cerebroside was altered in PLP(null) mice relative to wild-type (wt) animals. However, the yield of myelin from PLP(null) mice, assayed as levels of cerebroside, was only about 55% of wt control levels.

Alterations in metabolism and gene expression in brain regions during cuprizone-induced demyelination and remyelination.

Exposure of mice to the copper chelator, cuprizone, results in CNS demyelination. There is remyelination after removal of the metabolic insult. We present brain regional studies identifying corpus callosum as particularly severely affected; 65% of cerebroside is lost after 6 weeks of exposure.