CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development

Charged multivesicular body protein 1A (CHMP1A; also known as chromatin-modifying protein 1A) is a member of the ESCRT-III (endosomal sorting complex required for transport-III) complex but is also suggested to localize to the nuclear matrix and regulate chromatin structure. Here, we show that loss-of-function mutations in human CHMP1A cause reduced cerebellar size (pontocerebellar hypoplasia) and reduced cerebral cortical size (microcephaly). CHMP1A-mutant cells show impaired proliferation, with increased expression of INK4A, a negative regulator of stem cell proliferation. Chromatin immunoprecipitation suggests loss of the normal INK4A repression by BMI in these cells. Morpholino-based knockdown of zebrafish chmp1a resulted in brain defects resembling those seen after bmi1a and bmi1b knockdown, which were partially rescued by INK4A ortholog knockdown, further supporting links between CHMP1A and BMI1-mediated regulation of INK4A. Our results suggest that CHMP1A serves as a critical link between cytoplasmic signals and BMI1-mediated chromatin modifications that regulate proliferation of central nervous system progenitor cells

Control of Alzheimer's Amyloid Beta Toxicity by the High Molecular Weight Immunophilin FKBP52 and Copper Homeostasis in Drosophila

FK506 binding proteins (FKBPs), also called immunophilins, are prolyl-isomerases (PPIases) that participate in a wide variety of cellular functions including hormone signaling and protein folding. Recent studies indicate that proteins that contain PPIase activity can also alter the processing of Alzheimer's Amyloid Precursor Protein (APP). Originally identified in hematopoietic cells, FKBP52 is much more abundantly expressed in neurons, including the hippocampus, frontal cortex, and basal ganglia. Given the fact that the high molecular weight immunophilin FKBP52 is highly expressed in CNS regions susceptible to Alzheimer's, we investigated its role in Aβ toxicity. Towards this goal, we generated Aβ transgenic Drosophila that harbor gain of function or loss of function mutations of FKBP52. FKBP52 overexpression reduced the toxicity of Aβ and increased lifespan in Aβ flies, whereas loss of function of FKBP52 exacerbated these Aβ phenotypes. Interestingly, the Aβ pathology was enhanced by mutations in the copper transporters Atox1, which interacts with FKBP52, and Ctr1A and was suppressed in FKBP52 mutant flies raised on a copper chelator diet. Using mammalian cultures, we show that FKBP52 (−/−) cells have increased intracellular copper and higher levels of Aβ. This effect is reversed by reconstitution of FKBP52. Finally, we also found that FKBP52 formed stable complexes with APP through its FK506 interacting domain. Taken together, these studies identify a novel role for FKBP52 in modulating toxicity of Aβ peptides

The HIV Envelope but Not VSV Glycoprotein Is Capable of Mediating HIV Latent Infection of Resting CD4 T Cells

HIV fusion and entry into CD4 T cells are mediated by two receptors, CD4 and CXCR4. This receptor requirement can be abrogated by pseudotyping the virion with the vesicular stomatitis virus glycoprotein (VSV-G) that mediates viral entry through endocytosis. The VSV-G-pseudotyped HIV is highly infectious for transformed cells, although the virus circumvents the viral receptors and the actin cortex. In HIV infection, gp120 binding to the receptors also transduces signals. Recently, we demonstrated a unique requirement for CXCR4 signaling in HIV latent infection of blood resting CD4 T cells. Thus, we performed parallel studies in which the VSV-G-pseudotyped HIV was used to infect both transformed and resting T cells in the absence of coreceptor signaling. Our results indicate that in transformed T cells, the VSV-G-pseudotyping results in lower viral DNA synthesis but a higher rate of nuclear migration. However, in resting CD4 T cells, only the HIV envelope-mediated entry, but not the VSV-G-mediated endocytosis, can lead to viral DNA synthesis and nuclear migration. The viral particles entering through the endocytotic pathway were destroyed within 1–2 days. These results indicate that the VSV-G-mediated endocytotic pathway, although active in transformed cells, is defective and is not a pathway that can establish HIV latent infection of primary resting T cells. Our results highlight the importance of the genuine HIV envelope and its signaling capacity in the latent infection of blood resting T cells. These results also call for caution on the endocytotic entry model of HIV-1, and on data interpretation where the VSV-G-pseudotyped HIV was used for identifying HIV restriction factors in resting T cells

Optimization of Muscle Activity for Task-Level Goals Predicts Complex Changes in Limb Forces across Biomechanical Contexts

Optimality principles have been proposed as a general framework for understanding motor control in animals and humans largely based on their ability to predict general features movement in idealized motor tasks. However, generalizing these concepts past proof-of-principle to understand the neuromechanical transformation from task-level control to detailed execution-level muscle activity and forces during behaviorally-relevant motor tasks has proved difficult. In an unrestrained balance task in cats, we demonstrate that achieving task-level constraints center of mass forces and moments while minimizing control effort predicts detailed patterns of muscle activity and ground reaction forces in an anatomically-realistic musculoskeletal model. Whereas optimization is typically used to resolve redundancy at a single level of the motor hierarchy, we simultaneously resolved redundancy across both muscles and limbs and directly compared predictions to experimental measures across multiple perturbation directions that elicit different intra- and interlimb coordination patterns. Further, although some candidate task-level variables and cost functions generated indistinguishable predictions in a single biomechanical context, we identified a common optimization framework that could predict up to 48 experimental conditions per animal (n = 3) across both perturbation directions and different biomechanical contexts created by altering animals' postural configuration. Predictions were further improved by imposing experimentally-derived muscle synergy constraints, suggesting additional task variables or costs that may be relevant to the neural control of balance. These results suggested that reduced-dimension neural control mechanisms such as muscle synergies can achieve similar kinetics to the optimal solution, but with increased control effort (≈2×) compared to individual muscle control. Our results are consistent with the idea that hierarchical, task-level neural control mechanisms previously associated with voluntary tasks may also be used in automatic brainstem-mediated pathways for balance