We propose that the toxic gain-of-function of the polyQ-expanded Htt that causes dysfunction of cellular RNA processing contributes to the pathogenesis of HD.
Strikingly, we found that increased dosage of SLC2A3 delayed AO in an HD cohort of 987 individuals, and that this correlated with increased levels of GLUT3 in HD patient cells.
In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects.
Huntington disease (HD), caused by CAG expansion in the ubiquitously expressed huntingtin gene, is characterized by early dysfunction and death of striatal medium-sized spiny neurons (MSNs).
The aim was to lower Htt levels and to correct the behavioral, biochemical, and neuropathological deficits shown to be associated with the YAC128 mouse model of HD.
We review insights that have been gleaned from HD genetics, metabolism, and pathology; HD mouse and cell models; the structure, function and post-translational modification of normal and mutant huntingtin (htt) protein; gene expression profiles in HD cells and tissue; the neurotoxicy of mutant htt RNA; and the expression of an antisense transcript from the HD locus.
Since hairpin small interference RNA (shRNA) technology allows inhibition of specific gene expression in vitro and in vivo, vector-mediated expression of an shRNA directed to htt mRNA could form the basis of a new treatment modality for HD.
In summary, it seems that mutant huntingtin, probably in intermediate aggregate forms, has the potential to inhibit proteasome activity, but the global status of the system in HD brain tissue is not yet fully elucidated.
Finally, we show that topotecan treatment to HD mouse not only inhibits the expression of transgenic mutant huntingtin, but also at the same time induces the expression of Ube3a, an ubiquitin ligase linked to the clearance of mutant huntingtin.
Thus, to elucidate the mechanism underlying mutant htt-mediated alterations in neurotransmission, we investigated how Ca<sub>v</sub>2.2 is affected by full-length mutant htt expression in a mouse model of HD (BACHD).
Cardiac dysfunction in HD might be a primary consequence of peripherally expressed mutant huntingtin or secondary to either a general decline in health or the onset of neurological dysfunction.
Our study suggests that the dysregulation of Sp1-mediated huntingtin transcription, combining with mutant huntingtin's detrimental effect on other Sp1-mediated downstream gene function, may contribute to the pathogenesis of HD.
Trinucleotide (CAG) repeat expansion in the Huntingtin gene (HTT) results in the expression of misfolded Huntingtin protein (Htt), which contributes to the development of Huntington's disease.
We show that (I) the majority of proteins captured by mutant HTT RNA belong to the spliceosome pathway, (II) expression of mutant CAG repeat RNA induces mis-splicing in a HD cell model, (III) overexpression of one of the splice factors trapped by mutant HTT ameliorates the HD phenotype in a fly model and (VI) deregulated splicing occurs in human HD brain.
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disease caused by an expanded polyglutamine tract in the ubiquitously expressed huntingtin protein.
We demonstrated a down-regulation of the HTT gene itself in HD neural cells and identified three genes, the expression of which differs significantly in HD cells when compared with wild-type controls, namely CHCHD2, TRIM4 and PKIB.