Trinucleotide Repeat Expansion

Publication Title: 
Nature Chemical Biology

In polyglutamine (polyQ) diseases, only certain neurons die, despite widespread expression of the offending protein. PolyQ expansion may induce neurodegeneration by impairing proteostasis, but protein aggregation and toxicity tend to confound conventional measurements of protein stability. Here, we used optical pulse labeling to measure effects of polyQ expansions on the mean lifetime of a fragment of huntingtin, the protein that causes Huntington's disease, in living neurons.

Tsvetkov, Andrey S.
Arrasate, Montserrat
Barmada, Sami
Ando, D. Michael
Sharma, Punita
Shaby, Benjamin A.
Finkbeiner, Steven
Publication Title: 
East Asian Archives of Psychiatry: Official Journal of the Hong Kong College of Psychiatrists = Dong Ya Jing Shen Ke Xue Zhi: Xianggang Jing Shen Ke Yi Xue Yuan Qi Kan

Anticipation is a phenomenon in which successive generations within a family experience an earlier age of onset and a more severe form of a given illness. It has been observed in various neurological and psychiatric conditions, including bipolar disorder. The molecular basis of anticipation involves trinucleotide repeat expansions in genes, but this has not been conclusively demonstrated in bipolar disorder. The histories of 3 father-son pairs are presented.

Rajkumar, R. P.
Publication Title: 
EMBO molecular medicine

Loss of function of the FMR1 gene leads to fragile X syndrome (FXS), the most common form of intellectual disability. The loss of FMR1 function is usually caused by epigenetic silencing of the FMR1 promoter leading to expansion and subsequent methylation of a CGG repeat in the 5' untranslated region. Very few coding sequence variations have been experimentally characterized and shown to be causal to the disease. Here, we describe a novel FMR1 mutation and reveal an unexpected nuclear export function for the C-terminus of FMRP.

Okray, Zeynep
de Esch, Celine E. F.
Van Esch, Hilde
Devriendt, Koen
Claeys, Annelies
Yan, Jiekun
Verbeeck, Jelle
Froyen, Guy
Willemsen, Rob
de Vrij, Femke M. S.
Hassan, Bassem A.
Publication Title: 

OBJECTIVE: To examine the epigenetic basis of psychiatric symptoms and dysexecutive impairments in FMR1 premutation (PM: 55 to 199 CGG repeats) women. METHODS: A total of 35 FMR1 PM women aged between 22 and 55 years and 35 age- and IQ-matched women controls (CGG <45) participated in this study. All participants completed a range of executive function tests and self-reported symptoms of psychiatric disorders.

Cornish, Kim M.
Kraan, Claudine M.
Bui, Quang Minh
Bellgrove, Mark A.
Metcalfe, Sylvia A.
Trollor, Julian N.
Hocking, Darren R.
Slater, Howard R.
Inaba, Yoshimi
Li, Xin
Archibald, Alison D.
Turbitt, Erin
Cohen, Jonathan
Godler, David E.
Publication Title: 
Science (New York, N.Y.)

Huntington's disease (HD) is an inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. Transcriptional dysregulation has been implicated in HD pathogenesis. Here, we report that huntingtin interacts with the transcriptional activator Sp1 and coactivator TAFII130. Coexpression of Sp1 and TAFII130 in cultured striatal cells from wild-type and HD transgenic mice reverses the transcriptional inhibition of the dopamine D2 receptor gene caused by mutant huntingtin, as well as protects neurons from huntingtin-induced cellular toxicity.

Dunah, Anthone W.
Jeong, Hyunkyung
Griffin, April
Kim, Yong-Man
Standaert, David G.
Hersch, Steven M.
Mouradian, M. Maral
Young, Anne B.
Tanese, Naoko
Krainc, Dimitri
Publication Title: 
The Journal of Neuroscience: The Official Journal of the Society for Neuroscience

Huntington's disease (HD) results from polyglutamine expansion in huntingtin (htt), a protein with several consensus caspase cleavage sites. Despite the identification of htt fragments in the brain, it has not been shown conclusively that htt is cleaved by caspases in vivo. Furthermore, no study has addressed when htt cleavage occurs with respect to the onset of neurodegeneration. Using antibodies that detect only caspase-cleaved htt, we demonstrate that htt is cleaved in vivo specifically at the caspase consensus site at amino acid 552.

Wellington, Cheryl L.
Ellerby, Lisa M.
Gutekunst, Claire-Anne
Rogers, Danny
Warby, Simon
Graham, Rona K.
Loubser, Odell
van Raamsdonk, Jeremy
Singaraja, Roshni
Yang, Yu-Zhou
Gafni, Juliette
Bredesen, Dale
Hersch, Steven M.
Leavitt, Blair R.
Roy, Sophie
Nicholson, Donald W.
Hayden, Michael R.
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