Professor Ruth Luthi-Carter

Tel: 0116 252 2925     Email: relc3@le.ac.uk

Professor Ruth Luthi-Carter

Publications

Laboratory publications

Research

    Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a trinucleotide repeat expansion in the gene encoding huntingtin. This leads to the expression of a mutated form of the huntingtin protein with an abnormally long polyglutamine tract. One major axis of our ongoing research in LNGF devoted to understanding how this mutant huntingtin cause specific changes in gene expression.

    Transcriptomic analyses comprise a particularly rational approach to studying HD because both wild-type and mutant huntingtin are known to have the ability to regulate gene expression. However, the exact mechanisms underlying these effects are less clear due to the fact that huntingtin is known to interact with more than 100 transcriptional regulatory proteins. We have thus embraced a system approach for resolving the question of which gene regulatory mechanisms play crucial roles in the etiology of HD.

    Although predictions based on models of disease have been building for a number of years, our Hodges et al. 2006 study provided the first opportunity to assess the validity of these hypotheses with genome-wide RNA analyses of bona fide disease samples. Using laser-capture microdissection, we confirmed gene expression changes in HD-affected caudate neurons at an mRNA/cell level. Moreover, these analyses confirmed a suspected effect on neurotransmitter-related signaling processes and elucidated a novel regional specificity of disease-related mRNA changes (motor cortex [Broadmann area 4] >> prefrontal association cortex [Broadmann area 9]). More recent studies have also confirmed regional variant cerebral cortical effects in layer 5 pyramidal neurons (Zucker et al., 2010). Application of more sophisticated analysis methods to human microarray data has also identified cell-type-specific changes in both neuronal and glial cells (Kuhn et al., 2010). These studies make an important link back from model systems to human disease and provided the neurobiology research community with valuable benchmark RNA datasets and analyses.

    The caudate nucleus and the cerebral cortex are the major sites of neurodegeneration in HD. These two regions are connected by direct glutamatergic axonal projections from the cerebral cortex to the GABAergic medium spiny neurons, the striatal neuron type selectively lost in HD. Thus, many hypotheses have attempted to explain HD etiology by assessing potentially abnormal interactions between these two cell types, including increased glutamatergic neurotransmission leading to excitotoxicity and decreased BDNF-mediated trophic support. On the other hand, mutant huntingtin can exhibit toxicities to both striatal and cortical neurons independently, and therefore parallel effects of htt in both are also possible. Recent work has been undertaken by our laboratory and others to discriminate intracellular from transcellular events causing neurodegeneration in HD.

Current projects in the lab

  • Novel mechanisms of Huntington's diseaase-induced dysregulation of the brain-derived neurotrophic factor (BDNF) gene
  • Modulation of mutant huntingtin's detrimental effects by RGS2
  • Possible restoration of gene expression deficits in Huntington's disease by diminishing HDAC4 activity.
  • The Relation of Gene Expression in the Cerebral Cortex to Symptom Profile in Huntington’s disease
  • Dose-dependent neuronal effects of huntingtin silencing.
  • Prevention of neurodegeneration through nutritionally accessible regulation of gene expression
  • MAP kinase phosphatases 1 and 3 as candidate modifiers of Huntington’s disease neurotoxicity
  • Neuroprotective effects of SIRT2 inhibition in Huntington’s disease.
  • Neural cell-type-specific determinants of gene expression
  • Modeling gene regulation and peripheral phenotypes in Huntington's disease

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