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Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by progressive neuropathology and cognitive decline. We describe a cross-tissue analysis of methylomic variation in AD using samples from three independent human post-mortem brain cohorts. We identify a differentially methylated region in the ankyrin 1 (ANK1) gene that is associated with neuropathology in the entorhinal cortex, a primary site of AD manifestation. This region was confirmed as significantly hypermethylated in two other cortical regions (superior temporal gyrus and prefrontal cortex) but not in the cerebellum, a region largely protected from neurodegeneration in AD, nor whole blood obtained pre-mortem, from the same individuals. Neuropathology-associated ANK1 hypermethylation was subsequently confirmed in cortical samples from three independent brain cohorts. This study represents the first epigenome-wide association study (EWAS) of AD employing a sequential replication design across multiple tissues, and highlights the power of this approach for identifying methylomic variation associated with complex disease.

BackgroundSchizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated.ResultsWe performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts. We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts; these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia. Finally, we show how DNA methylation quantitative trait loci in combination with Bayesian co-localization analyses can be used to annotate extended genomic regions nominated by studies of schizophrenia, and to identify potential regulatory variation causally involved in disease.ConclusionsThis study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological approach that can be used to inform epigenome-wide association study analyses of other complex traits and diseases. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with etiological variation, and of using DNA methylation quantitative trait loci to refine the functional and regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1041-x) contains supplementary material, which is available to authorized users.

Spectrin is a vital component of the cytoskeleton, conferring flexibility on cells and providing a scaffold for a variety of proteins. It is composed of tandem, antiparallel coiled-coil repeats. We report four related crystal structures at 1.45 A, 2.0 A, 3.1 A, and 4.0 A resolution of two connected repeats of chicken brain alpha-spectrin. In all of the structures, the linker region between adjacent units is alpha-helical without breaks, kinks, or obvious boundaries. Two features observed in the structures are (1) conformational rearrangement in one repeat, resulting in movement of the position of a loop, and (2) varying degrees of bending at the linker region. These features form the basis of two different models of flexibility: a conformational rearrangement and a bending model. These models provide novel atomic details of spectrin flexibility.

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Erythroid spectrin, a major component of the cytoskeletal network of the red cell which contributes to both the stability and the elasticity of the red cell membrane, is composed of two subunits, alpha and beta, each formed by 16-20 tandem repeats. The properties of the repeats and their relative arrangement are thought to be key determinants of spectrin flexibility. Here we report a 2.4 A resolution crystal structure of human erythroid beta-spectrin repeats 8 and 9. This two-repeat fragment is unusual as it exhibits low stability of folding and one of its repeats lacks two tryptophans highly conserved among spectrin repeats. Two key factors responsible for the lower stability and, possibly, its flexibility, are revealed by the structure. A third novel feature of the structure is the relative orientation of the two repeats, which increases the range of possible conformations and provides new insights into atomic models of spectrin flexibility.

Mitochondrial abnormalities have been identified as a central mechanism in multiple neurodegenerative diseases and, therefore, the mitochondria have been explored as a therapeutic target. This review will focus on the evidence for mitochondrial abnormalities in the two most common neurodegenerative diseases, Parkinson's disease and Alzheimer's disease. In addition, we discuss the main strategies which have been explored in these diseases to target the mitochondria for therapeutic purposes, focusing on mitochondrially targeted antioxidants, peptides, modulators of mitochondrial dynamics and phenotypic screening outcomes.

Free energies of both urea and thermal denaturation have been measured for three pairs of one- and two-repeat fragments, cloned in tandem from the cytoskeletal protein, alpha-spectrin, from chicken brain to ascertain whether one- and two-repeat fragments are equally stable. One- and two-repeat fragments of each pair were designed with the same N-terminus, whereas the C-terminus of the two-repeat fragment was 106 residues or the length of one repeat downstream from that of the one-repeat fragment. The averaged free energies of urea and thermal denaturation of the paired fragments, (R16)(00) and (R16R17)(00), (R16)(0+3) and (R16R17)(0+3), and (R16)(+8-4) and (R16R17)(+8-4) [subscripts represent the N- and C-terminal positions with "00" referring to the N- and C-termini defining a repeat according to X-ray crystal structures of two repeat fragments [Grum, V. L., Li, D., MacDonald, R. I., and Mondragón, A. (1999) Cell 98, 523-535] and "+" and "-" referring to positions upstream and downstream therefrom, respectively], increased from 3.7 +/- 0.4 kcal/mol for (R16)(00), 3.7 +/- 0.5 kcal/mol for (R16)(0+3), 4.4 +/- 0.4 kcal/mol for (R16)(+8-4), 6.2 +/- 0.6 kcal/mol for (R16R17)(+8-4), 8.3 +/- 0.4 kcal/mol for (R16R17)(00) to 9.9 +/- 1.0 kcal/mol for (R16R17)(0+3). Thus, the two-repeat fragment of each pair was significantly more thermodynamically stable than the single repeat by both urea and thermal denaturation. Differences in phasing among single repeats did not have the same effect as the same differences in phasing among two-repeat fragments. Addition of nine residues to the C-terminus of (R16R17)(00) yielded a free energy of unfolding of 7.9 +/- 0.8 kcal/mol, whereas addition of seven residues to the C-terminus of (R16)(+8-4) yielded a free energy of unfolding of 5.9 +/- 0.3 kcal/mol.