neurodegeneration

Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

Transcriptional dysregulation is an early feature of Huntington disease (HD). We observed gene-specific changes in histone H3 lysine 4 trimethylation (H3K4me3) at transcriptionally repressed promoters in R6/2 mouse and human HD brain. Genome-wide analysis showed a chromatin signature for this mark. Reducing the levels of the H3K4 demethylase SMCX/Jarid1c in primary neurons reversed down-regulation of key neuronal genes caused by mutant Huntingtin expression. Finally, reduction of SMCX/Jarid1c in primary neurons from BACHD mice or the single Jarid1 in a Drosophila HD model was protective.

Author(s): 
Vashishtha, Malini
Ng, Christopher W.
Yildirim, Ferah
Gipson, Theresa A.
Kratter, Ian H.
Bodai, Laszlo
Song, Wan
Lau, Alice
Labadorf, Adam
Vogel-Ciernia, Annie
Troncosco, Juan
Ross, Christopher A.
Bates, Gillian P.
Krainc, Dimitri
Sadri-Vakili, Ghazaleh
Finkbeiner, Steven
Marsh, J. Lawrence
Housman, David E.
Fraenkel, Ernest
Thompson, Leslie M.
Publication Title: 
Biological Psychiatry

Nuclear transplantation, cell fusion, and induced pluripotent stem cell studies have revealed a surprising degree of plasticity in mature mammalian cell fates. Somatic cell reprogramming also has been achieved more recently by the directed conversion of nonneuronal somatic cells, such as skin fibroblasts, to neuronal phenotypes. This approach appears particularly applicable to the in vitro modeling of human neurologic disorders.

Author(s): 
Qiang, Liang
Inoue, Keiichi
Abeliovich, Asa
Publication Title: 
Dialogues in Clinical Neuroscience

Epigenetics, broadly defined as the regulation of gene expression without alteration of the genome, has become a field of tremendous interest in neuroscience, neurology, and psychiatry. This research has rapidly changed the way researchers think about brain function. Exciting epigenetic discoveries have been found in addiction, early life stress, neurodegeneration, post-traumatic stress disorder, and depression.

Author(s): 
Abel, Ted
Poplawski, Shane
Publication Title: 
Cell Cycle (Georgetown, Tex.)

Abnormal protein interactions of mutant huntingtin (Htt) triggered by polyglutamine expansion are thought to mediate Huntington's disease (HD) pathogenesis. Here, we explored a functional interaction of Htt with protein arginine methyltransferase 5 (PRMT5), an enzyme mediating symmetrical dimethylation of arginine (sDMA) of key cellular proteins, including histones, and spliceosomal Sm proteins. Gene transcription and RNA splicing are impaired in HD. We demonstrated PRMT5 and Htt interaction and their co-localization in transfected neurons and in HD brain.

Author(s): 
Ratovitski, Tamara
Arbez, Nicolas
Stewart, Jacqueline C.
Chighladze, Ekaterine
Ross, Christopher A.
Publication Title: 
Progress in Neurobiology

Epigenetics is a quickly growing field encompassing mechanisms regulating gene expression that do not involve changes in the genotype. Epigenetics is of increasing relevance to neuroscience, with epigenetic mechanisms being implicated in brain development and neuronal differentiation, as well as in more dynamic processes related to cognition. Epigenetic regulation covers multiple levels of gene expression; from direct modifications of the DNA and histone tails, regulating the level of transcription, to interactions with messenger RNAs, regulating the level of translation.

Author(s): 
Lardenoije, Roy
Iatrou, Artemis
Kenis, Gunter
Kompotis, Konstantinos
Steinbusch, Harry W. M.
Mastroeni, Diego
Coleman, Paul
Lemere, Cynthia A.
Hof, Patrick R.
van den Hove, Daniel L. A.
Rutten, Bart P. F.
Publication Title: 
Brain Research

The rapidly evolving science of epigenetics is transforming our understanding of the nervous system in health and disease and holds great promise for the development of novel diagnostic and therapeutic approaches targeting neurological diseases. Increasing evidence suggests that epigenetic factors and mechanisms serve as important mediators of the pathogenic processes that lead to irrevocable neural injury and of countervailing homeostatic and regenerative responses. Epigenetics is, therefore, of considerable translational significance to the field of neuroprotection.

Author(s): 
Qureshi, Irfan A.
Mehler, Mark F.
Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

Recent studies have identified impairments in neural induction and in striatal and cortical neurogenesis in Huntington's disease (HD) knock-in mouse models and associated embryonic stem cell lines. However, the potential role of these developmental alterations for HD pathogenesis and progression is currently unknown. To address this issue, we used BACHD:CAG-Cre(ERT2) mice, which carry mutant huntingtin (mHtt) modified to harbor a floxed exon 1 containing the pathogenic polyglutamine expansion (Q97).

Author(s): 
Molero, Aldrin E.
Arteaga-Bracho, Eduardo E.
Chen, Christopher H.
Gulinello, Maria
Winchester, Michael L.
Pichamoorthy, Nandini
Gokhan, Solen
Khodakhah, Kamran
Mehler, Mark F.
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