Self-awareness of executive dysfunction in Huntington's disease: comparison with Parkinson's disease and cervical dystonia.

This study assessed self-awareness of executive deficits in patients with Huntington's disease (HD) in comparison to patients with Parkinson's disease (PD) and with cervical dystonia (CD). Eighty-nine patient-proxy pairs participated in the study (23 with HD, 25 with advanced PD, 21 with mild PD and 20 with CD). Executive function was assessed with the Stroop test and the Dysexecutive Questionnaire. Insight into executive impairment in HD is mildly affected, when compared to PD and CD.

Self-awareness of motor dysfunction in patients with Huntington's disease in comparison to Parkinson's disease and cervical dystonia.

Individuals suffering from Huntington's disease (HD) have been shown to present with poor self-awareness of a variety of symptoms. The aim of this study was to better assess the self-awareness of motor symptoms and activities of daily living (ADL) impairment in HD, in comparison to Parkinson's disease (PD) and cervical dystonia (CD). In particular, the anosognosia/anosodiaphoria of involuntary movements has been investigated. Self-awareness was tested in 23 patients with HD by comparing patient and caregiver ratings in reference to clinical control groups (25 PD with dyskinesias, PDdys; 21 PD without dyskinesias, PDndys; and 20 with CD). Patients were assessed neurologically by relevant rating scales. Self-awareness was tested using a scale based on 15 films demonstrating 3 types of motor symptoms (chorea/dyskinesias, parkinsonism, torticollis) as well as the Self-Assessment Parkinson's Disease Disability Scale. General cognitive status, verbal learning, cognitive control, and mood were also analyzed. Our results indicate that self-awareness of choreic movements was affected more severely in HD than in PDdys, despite comparable cognitive status. Patient-proxy agreement on ADL impairment was roughly similar in all clinical groups. The results are discussed in the context of orbitofrontal-limbic pathology as a potential trigger of anosognosia/anosodiaphoria in individuals with HD.

Saccharomyces cerevisiae phospholipase C regulates transcription of Msn2p-dependent stress-responsive genes.

Phosphatidylinositol phosphates are involved in signal transduction, cytoskeletal organization, and membrane trafficking. Inositol polyphosphates, produced from phosphatidylinositol phosphates by the phospholipase C-dependent pathway, regulate chromatin remodeling. We used genome-wide expression analysis to further investigate the roles of Plc1p (phosphoinositide-specific phospholipase C in Saccharomyces cerevisiae) and inositol polyphosphates in transcriptional regulation. Plc1p contributes to the regulation of approximately 2% of yeast genes in cells grown in rich medium. Most of these genes are induced by nutrient limitation and other environmental stresses and are derepressed in plc1 Delta cells. Surprisingly, genes regulated by Plc1p do not correlate with gene sets regulated by Swi/Snf or RSC chromatin remodeling complexes but show correlation with genes controlled by Msn2p. Our results suggest that the increased expression of stress-responsive genes in plc1 Delta cells is mediated by decreased cyclic AMP synthesis and protein kinase A (PKA)-mediated phosphorylation of Msn2p and increased binding of Msn2p to stress-responsive promoters. Accordingly, plc1 Delta cells display other phenotypes characteristic of cells with decreased PKA activity. Our results are consistent with a model in which Plc1p acts together with the membrane receptor Gpr1p and associated G(alpha) protein Gpa2p in a pathway separate from Ras1p/Ras2p and converging on PKA.

Role of Plc1p in regulation of Mcm1p-dependent genes.

In budding yeasts, phosphoinositide-specific phospholipase C (Plc1p encoded by PLC1 gene) and several inositol polyphosphate kinases represent a nuclear pathway for synthesis of inositol polyphosphates (InsPs), which are involved in several aspects of DNA and RNA metabolism, including transcriptional regulation. Plc1p-produced inositol trisphosphate (InsP(3)) is phosphorylated by Ipk2p/Arg82p to yield InsP(4)/InsP(5). Ipk2p/Arg82p is also a component of ArgR-Mcm1p complex that regulates transcription of genes involved in arginine metabolism. The role of Ipk2p/Arg82p in this complex is to stabilize the essential MADS box protein Mcm1p. Consequently, ipk2Delta cells display reduced levels of Mcm1p and attenuated expression of Mcm1p-dependent genes. Because plc1Delta cells display aberrant expression of several groups of genes, including genes involved in stress response, the objective of this study was to determine whether Plc1p also affects expression of Mcm1p-dependent genes. Here we report that not only ipk2Delta, but also plc1Delta cells display decreased expression of Mcm1p-dependent genes. However, Plc1p is not involved in stabilization of Mcm1p and affects transcription of Mcm1p-dependent genes by a different mechanism, probably involving regulation of chromatin remodeling complexes.