Neuroimaging Studies of Brain Structure in Older Adults with Bipolar Disorder: A Review.

Bipolar disorder (BD) is a common mood disorder that can have severe consequences during later life, including suffering and impairment due to mood and cognitive symptoms, elevated risk for dementia and an especially high risk for suicide. Greater understanding of the brain circuitry differences involved in older adults with BD (OABD) in later life and their relationship to aging processes is required to improve outcomes of OABD. The current literature on gray and white matter findings, from high resolution structural and diffusion-weighted magnetic resonance imaging (MRI) studies, has shown that BD in younger age groups is associated with gray matter reductions within cortical and subcortical brain regions that subserve emotion processing and regulation, as well as reduced structural integrity of white matter tracts connecting these brain regions. While fewer neuroimaging studies have focused on OABD, it does appear that many of the structural brain differences found in younger samples are present in OABD. There is also initial suggestion that there are additional brain differences, for at least a subset of OABD, that may result from more pronounced gray and white matter declines with age that may contribute to adverse outcomes. Preclinical and clinical data supporting neuro-plastic and -protective effects of mood-stabilizing medications, suggest that treatments may reverse and/or prevent the progression of brain changes thereby reducing symptoms. Future neuroimaging research implementing longitudinal designs, and large-scale, multi-site initiatives with detailed clinical and treatment data, holds promise for reducing suffering, cognitive dysfunction and suicide in OABD.

Crystal Structures of Ternary Complexes of MEF2 and NKX2-5 Bound to DNA Reveal a Disease Related Protein-Protein Interaction Interface.

MEF2 and NKX2-5 transcription factors interact with each other in cardiogenesis and are necessary for normal heart formation. Despite evidence suggesting that these two transcription factors function synergistically and possibly through direct physical interactions, molecular mechanisms by which they interact are not clear. Here we determined the crystal structures of ternary complexes of MEF2 and NKX2-5 bound to myocardin enhancer DNA in two crystal forms. These crystal structures are the first example of human MADS-box/homeobox ternary complex structures involved in cardiogenesis. Our structures reveal two possible modes of interactions between MEF2 and NKX2-5: MEF2 and NKX bind to adjacent DNA sites to recognize DNA in cis; and MEF2 and NKX bind to different DNA strands to interact with each other in trans via a conserved protein-protein interface observed in both crystal forms. Disease-related mutations are mapped to the observed protein-protein interface. Our structural studies provide a starting point to understand and further study the molecular mechanisms of the interactions between MEF2 and NKX2.5 and their roles in cardiogenesis.

Crystal Structure of Apo MEF2B Reveals New Insights in DNA Binding and Cofactor Interaction.

The myocyte enhancer factor 2 (MEF2) family of transcription factors plays important roles in developmental processes and adaptive responses. Although MEF2 proteins are known to bind DNA in the nucleus to regulate specific gene expression, there are reports that show that MEF2 also functions in the cytoplasm. Previous structural studies of MEF2 focused exclusively on DNA-bound MEF2 with and without various corepressors or coactivators. While these studies have established a comprehensive structural model of DNA recognition and cofactor recruitment by MEF2, the structure of MEF2 not bound to DNA, which include cytoplasmic MEF2 and free MEF2 in the nucleus, is unknown. Here we determined the structure of the MADS-box/MEF2 domain of MEF2B without DNA nor cofactor. The Apo structure of MEF2B reveals a largely preformed DNA binding interface that may be important for recognizing the shape of DNA from the minor groove side. In addition, our structure also reveals that the C-terminal helix of the MEF2-specific domain could flip up to bind to the hydrophobic groove that serves as the binding sites of MEF2 transcription cofactors. These observations shed new insights into DNA binding and cofactor interaction by MEF2 proteins.

The Cancer Mutation D83V Induces an α-Helix to ß-Strand Conformation Switch in MEF2B.

MEF2B is a major target of somatic mutations in non-Hodgkin lymphoma. Most of these mutations are non-synonymous substitutions of surface residues in the MADS-box/MEF2 domain. Among them, D83V is the most frequent mutation found in tumor cells. The link between this hotspot mutation and cancer is not well understood. Here we show that the D83V mutation induces a dramatic α-helix to ß-strand switch in the MEF2 domain. Located in an α-helix region rich in ß-branched residues, the D83V mutation not only removes the extensive helix stabilization interactions but also introduces an additional ß-branched residue that further shifts the conformation equilibrium from α-helix to ß-strand. Cross-database analyses of cancer mutations and chameleon sequences revealed a number of well-known cancer targets harboring ß-strand favoring mutations in chameleon α-helices, suggesting a commonality of such conformational switch in certain cancers and a new factor to consider when stratifying the rapidly expanding cancer mutation data.