Summary Astrocytes are ubiquitous in the brain and are widely held to be largely identical. However, this view has not been fully tested and the possibility that astrocytes are neural circuit-specialized remains largely unexplored. Here, we used multiple, integrated approaches including RNA-Seq, mass spectrometry, electrophysiology, immunohistochemistry, serial block-face scanning electron microscopy, morphological reconstructions, pharmacogenetics, as well as diffusible dye, calcium and glutamate imaging, to directly compare adult striatal and hippocampal astrocytes under identical conditions. We found significant differences between striatal and hippocampal astrocytes in electrophysiological properties, Ca2+ signaling, morphology and astrocyte-synapse proximity. Unbiased evaluation of actively translated RNA and proteomic data confirmed significant astrocyte diversity between hippocampal and striatal circuits. We thus report core astrocyte properties, reveal evidence for specialized astrocytes within neural circuits and provide new, integrated database resources and approaches to explore astrocyte diversity and function throughout the adult brain.

Vitamin A has diverse biological functions. It is transported in the blood as a complex with retinol binding protein (RBP), but the molecular mechanism by which vitamin A is absorbed by cells from the vitamin A-RBP complex is not clearly understood. We identified in bovine retinal pigment epithelium cells STRA6, a multitransmembrane domain protein, as a specific membrane receptor for RBP. STRA6 binds to RBP with high affinity and has robust vitamin A uptake activity from the vitamin A-RBP complex. It is widely expressed in embryonic development and in adult organ systems. The RBP receptor represents a major physiological mediator of cellular vitamin A uptake.

Amyloid diseases, including Alzheimer's, Parkinson's, and the prion conditions, are each associated with a particular protein in fibrillar form. These amyloid fibrils were long suspected to be the disease agents, but evidence suggests that smaller, often transient and polymorphic oligomers are the toxic entities. Here we identify a segment of the amyloid-forming protein, alphaB crystallin, which forms an oligomeric complex exhibiting properties of other amyloid oligomers: beta-sheet-rich structure, cytotoxicity, and recognition by an anti-oligomer antibody. The X-ray-derived atomic structure of the oligomer reveals a cylindrical barrel, formed from six anti-parallel, protein strands, which we term a cylindrin. The cylindrin structure is compatible with a sequence segment from the Abeta protein of Alzheimer's disease. Cylindrins offer models for the hitherto elusive structures of amyloid oligomers.

Summary The protein α-synuclein is the main component of Lewy bodies, the neuron-associated aggregates seen in Parkinson’s disease and other neurodegenerative pathologies. An 11-residue segment, which we term NACore, appears responsible for amyloid formation and cytotoxicity of α-synuclein. Here we report crystals of NACore having dimensions smaller than the wavelength of visible light and thus invisible by optical microscopy. Thousands of times too small for structure determination by synchrotron x-ray diffraction, these crystals have yielded an atomic resolution structure by the frontier method of Micro-Electron Diffraction. The 1.4 Å resolution structure demonstrates for the first time that this method can determine previously unknown protein structures and here yields the highest resolution achieved by any cryo-electron microscopy method to date. The structure reveals protofibrils built of pairs of face-to-face β-sheets. X-ray fiber diffraction patterns show the similarity of NACore to toxic fibrils of full-length α-synuclein. The NACore structure, together with that of a second segment, inspires a model for most of the ordered portion of the toxic, full-length α-synuclein fibril, opening opportunities for design of inhibitors of α-synuclein fibrils.