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  • : Operationalizing compensation over time in neurodegenerative disease. - pubmed: huntington's or hunt...

    Operationalizing compensation over time in neurodegenerative disease.

    Brain. 2017 Feb 23;:

    Authors: Gregory S, Long JD, Klöppel S, Razi A, Scheller E, Minkova L, Papoutsi M, Mills JA, Durr A, Leavitt BR, Roos RA, Stout JC, Scahill RI, Langbehn DR, Tabrizi SJ, Rees G

    PMID: 28334888 [PubMed - as supplied by publisher]

  • : High resolution time-course mapping of early transcriptomic, molecular and cellular phenotypes in Huntington's disease CAG knock-in mice across multiple genetic backgrounds. - pubmed: huntington's or hunt...

    High resolution time-course mapping of early transcriptomic, molecular and cellular phenotypes in Huntington's disease CAG knock-in mice across multiple genetic backgrounds.

    Hum Mol Genet. 2017 Feb 27;:

    Authors: Ament SA, Pearl JR, Grindeland A, St Claire J, Earls JC, Kovalenko M, Gillis T, Mysore J, Gusella JF, Lee JM, Kwak S, Howland D, Lee MY, Baxter D, Scherler K, Wang K, Geman D, Carroll JB, MacDonald ME, Carlson G, Wheeler VC, Price ND, Hood LE

    Abstract
    Huntington's disease is a dominantly inherited neurodegenerative disease caused by the expansion of a CAG repeat in the HTT gene. In addition to the length of the CAG expansion, factors such as genetic background have been shown to contribute to the age at onset of neurological symptoms. A central challenge in understanding the disease progression that leads from the HD mutation to massive cell death in the striatum is the ability to characterize the subtle and early functional consequences of the CAG expansion longitudinally. We used dense time course sampling between 4 and 20 postnatal weeks to characterize early transcriptomic, molecular and cellular phenotypes in the striatum of six distinct knock-in mouse models of the HD mutation. We studied the effects of the HttQ111 allele on the C57BL/6J, CD-1, FVB/NCr1, and 129S2/SvPasCrl genetic backgrounds, and of two additional alleles, HttQ92 and HttQ50, on the C57BL/6J background. We describe the emergence of a transcriptomic signature in HttQ111/+  mice involving hundreds of differentially expressed genes and changes in diverse molecular pathways. We also show that this time course spanned the onset of mutant huntingtin nuclear localization phenotypes and somatic CAG-length instability in the striatum. Genetic background strongly influenced the magnitude and age at onset of these effects. This work provides a foundation for understanding the earliest transcriptional and molecular changes contributing to HD pathogenesis.

    PMID: 28334820 [PubMed - as supplied by publisher]

  • : CTG repeat-targeting oligonucleotides for down-regulating Huntingtin expression. - pubmed: huntington's or hunt...

    CTG repeat-targeting oligonucleotides for down-regulating Huntingtin expression.

    Nucleic Acids Res. 2017 Feb 17;:

    Authors: Zaghloul EM, Gissberg O, Moreno PM, Siggens L, Hällbrink M, Jørgensen AS, Ekwall K, Zain R, Wengel J, Lundin KE, Smith CI

    Abstract
    Huntington's disease (HD) is a fatal, neurodegenerative disorder in which patients suffer from mobility, psychological and cognitive impairments. Existing therapeutics are only symptomatic and do not significantly alter the disease progression or increase life expectancy. HD is caused by expansion of the CAG trinucleotide repeat region in exon 1 of the Huntingtin gene (HTT), leading to the formation of mutant HTT transcripts (muHTT). The toxic gain-of-function of muHTT protein is a major cause of the disease. In addition, it has been suggested that the muHTT transcript contributes to the toxicity. Thus, reduction of both muHTT mRNA and protein levels would ideally be the most useful therapeutic option. We herein present a novel strategy for HD treatment using oligonucleotides (ONs) directly targeting the HTT trinucleotide repeat DNA. A partial, but significant and potentially long-term, HTT knock-down of both mRNA and protein was successfully achieved. Diminished phosphorylation of HTT gene-associated RNA-polymerase II is demonstrated, suggestive of reduced transcription downstream the ON-targeted repeat. Different backbone chemistries were found to have a strong impact on the ON efficiency. We also successfully use different delivery vehicles as well as naked uptake of the ONs, demonstrating versatility and possibly providing insights for in vivo applications.

    PMID: 28334749 [PubMed - as supplied by publisher]

  • : Mutant Exon1 Huntingtin Aggregation is Regulated by T3 Phosphorylation-Induced Structural Changes and Crosstalk between T3 Phosphorylation and Acetylation at K6. - pubmed: huntington's or hunt...

    Mutant Exon1 Huntingtin Aggregation is Regulated by T3 Phosphorylation-Induced Structural Changes and Crosstalk between T3 Phosphorylation and Acetylation at K6.

    Angew Chem Int Ed Engl. 2017 Mar 23;:

    Authors: Chiki A, DeGuire SM, Ruggeri FS, Sanfelice D, Ansaloni A, Wang ZM, Cendrowska U, Burai R, Vieweg S, Pastore A, Dietler G, Lashuel HA

    Abstract
    Herein, we used protein semisynthesis to investigate, for the first time, the effect of lysine acetylation and phosphorylation, as well as the crosstalk between these modifications on the structure and aggregation of mutant huntingtin exon1 (Httex1). Our results demonstrate that phosphorylation at T3 stabilizes the α-helical conformation of the N-terminal 17 amino acids (Nt17) and significantly inhibits the aggregation of mutant Httex1. Acetylation of single lysine residues, K6, K9 or K15, had no effect on Httex1 aggregation. Interestingly, acetylation at K6, but not at K9 or K15, reversed the inhibitory effect of T3 phosphorylation. Together, our results provide novel insight into the role of Nt17 post-translational modifications in regulating the structure and aggregation of Httex1 and suggest that its aggregation and possibly its function(s) are controlled by regulatory mechanisms involving crosstalk between different PTMs.

    PMID: 28334491 [PubMed - as supplied by publisher]

  • : Patterns of False Memory in Patients with Huntington's Disease. - pubmed: huntington's or hunt...

    Patterns of False Memory in Patients with Huntington's Disease.

    Arch Clin Neuropsychol. 2017 Mar 17;:1-10

    Authors: Chen IW, Chen CM, Wu YR, Hua MS

    Abstract
    Objective: Increased false memory recognition in patients with Huntington's disease (HD) has been widely reported; however, the underlying memory constructive processes remain unclear. The present study explored gist memory, item-specific memory, and monitoring ability in patients with HD.
    Method: Twenty-five patients (including 13 patients with mild HD and 12 patients with moderate-to-severe HD) and 30 healthy comparison participants (HC) were recruited. We used the Deese-Roediger-McDermott (DRM) paradigm to investigate participants' false recognition patterns, along with neuropsychological tests to assess general cognitive function.
    Results: Both mild and moderate-to-severe patients with HD showed significant executive functioning and episodic memory impairment. On the DRM tasks, both HD patient groups showed significantly impaired performance in tasks assessing unrelated false recognition and item-specific memory as compared to the HC group; moderate-to-severe patients performed more poorly than mild patients did. Only moderate-severe patients exhibited significantly poorer related false recognition index scores than HCs in the verbal DRM task; performance of HD patient groups was comparable to the HC group on the pictorial DRM task.
    Conclusions: It appears that diminished verbatim memory and monitoring ability are early signs of cognitive decline during the HD course. Conversely, gist memory is relatively robust, with only partial decline during advanced-stage HD. Our findings suggest that medial temporal lobe function is relatively preserved compared to that of frontal-related structures in early HD. Thus, gist-based memory rehabilitation programs might be beneficial for patients with HD.

    PMID: 28334378 [PubMed - as supplied by publisher]