The Actin-Binding Protein Capulet Genetically Interacts with the Microtubule Motor Kinesin to Maintain Neuronal Dendrite Homeostasis

BACKGROUND: Neurons require precise cytoskeletal regulation within neurites, containing microtubule tracks for cargo transport in axons and dendrites or within synapses containing organized actin. Due to the unique architecture and specialized function of neurons, neurons are particularly susceptible to perturbation of the cytoskeleton. Numerous actin-binding proteins help maintain proper cytoskeletal regulation. METHODOLOGY/PRINCIPAL FINDINGS: From a Drosophila forward genetic screen, we identified a mutation in capulet--encoding a conserved actin-binding protein--that causes abnormal aggregates of actin within dendrites. Through interaction studies, we demonstrate that simultaneous genetic inactivation of capulet and kinesin heavy chain, a microtubule motor protein, produces elongate cofilin-actin rods within dendrites but not axons. These rods resemble actin-rich structures induced in both mammalian neurodegenerative and Drosophila Alzheimer's models, but have not previously been identified by loss of function mutations in vivo. We further demonstrate that mitochondria, which are transported by Kinesin, have impaired distribution along dendrites in a capulet mutant. While Capulet and Cofilin may biochemically cooperate in certain circumstances, in neuronal dendrites they genetically antagonize each other. CONCLUSIONS/SIGNIFICANCE: The present study is the first molecularly defined loss of function demonstration of actin-cofilin rods in vivo. This study suggests that simultaneous, seemingly minor perturbations in neuronal dendrites can synergize producing severe abnormalities affecting actin, microtubules and mitochondria/energy availability in dendrites. Additionally, as >90% of Alzheimer's and Parkinson's cases are sporadic this study suggests mechanisms by which multiple mutations together may contribute to neurodegeneration instead of reliance on single mutations to produce disease

CCDC 229683: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

CCDC 229684: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

Conserved hydrogen-bonded supramolecular synthons in pyridinium tetrachlorometallates

The crystal and molecular structures of the pyridinium tetrahalometallates, [Hpy]2[CoCl4] and [Etpy]2[CoCl4], have been determined and compared with those of other pyridinium tetrahalometallates and 4,4'-bipyridinium perhalometallates. The pyridinium cation in [Hpy]2[CoCl4] uses its heterocyclic N–H and 4-positioned C–H moieties to form bifurcated hydrogen-bonds to tetrahalometallate anions and thus generate organic–inorganic hybrid solids similar in composition to those formed by 4,4-bipyridinium perhalometallate salts. Although the supramolecular synthons based on C–H donors are longer, and by inference, less strong, than those based on N–H donors, they are nonetheless, structure determining. The hydrogen-bonding capability of the ethylpyridinium cation is restricted to C–H donors and hence is not structure determining, the layered hexagonal network structure of [Etpy]2[CoCl4] being dominated by π–π stacking interactions

1-(4-Pyridinio)-2 '-[4-pyridinio-(E)-methylidene]-hydrazide dinitrate

The title compound, C12H12N4O2+·2NO3-, crystallizes as 1-(4-pyridinio)-2'-[4-pyridinio-(E)-methyl­idene]­hydrazide cations and nitrate anions. An extensive hydrogen-bonding network, primarily N-H...O interactions, but with supporting C-H...O contacts, leads to a three-dimensional matrix structure, which is best considered as a cationic framework with bridging nitrate anions. The basic feature of the cationic framework is a zigzag chain, which runs along the [101] direction. The chains pack to generate two-dimensional sheets which lie parallel to the (101) plane and stack in the [\overline 101] direction to give the three-dimensional matrix

CCDC 686096: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures