Huntingtin

In Huntington s disease the polyglutamine repeat expansion in exon 1 of HD leads to a toxic gain of the protein huntingtin (htt). Harper et al. could show that siRNA directed against mutant human htt reduced htt iriRNA and protein expression in cell culture and in HD... 

DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, Aronin N. Aggregation of Huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 1997 277 1990-1993. 

Amyloid precursor protein (APP), presenilin-1, presenilin-2, parkin, tau, huntingtin, ataxin-3... 

Polyglutamine Huntingtin Reverse-turn /1-sheet Sharma et al. (2005)... 

Figure 18.10 Characteristic inclusion bodies in neurodegenerative diseases, all labelled with antibodies (except (d)) as indicated, (a) and (b) HD intranuclear inclusion labelled for ubiquitin and huntingtin (cerebral cortex), (c) and (d) AD neuritic plaque labelled with AP (cerebral cortex) and silver stained, (e) and (f) PD, Lewy bodies labelled for ot-synuclein and phosphorylated a-synuclein (substantia nigra), (g) and (h) ALS labelled with ubiquitin and neurofilaments (medulla oblongata). (From Ross and Poirier, 2004. Reproduced by permission of Nature Publishing Group.)...

Alterations in brain iron metabolism have been reported, resulting in increased iron accumulation in Huntington s disease. This was particularly the case in basal ganglia from patients with HD compared to normal controls. In studies in embryonic stem cells, huntingtin was found to be iron-regulated, essential for the function of normal nuclear and perinuclear organelles and to be involved in the regulation of iron homeostasis. 

HD is caused by polyQ expansion in the amino-terminal region of a protein huntingtin (Htt). Disruption of the HD gene in mice causes increased neuronal apoptosis and progressive behavioural and motor dysfunction reminiscent of the disease in humans (Sanchez et al., 1999) but the exact molecular mechanisms... 

Boutell JM, Thomas P, Neal JW, Weston VJ, Duce J, Harper PS, Jones AL (1999) Aberrant interactions of transcriptional repressor proteins with the Huntington s disease gene product, huntingtin. Hum Mol Genet 8(9) 1647-1655... 

Gervais FG, Singaraja R, Xanthoudakis S, Gutekunst CA, Leavitt BR, Metzler M, Hackam AS, Tam J, Vaillancourt JP, Houtzager V, Rasper DM, Roy S, Hayden MR, Nicholson DW (2002) Recruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner Hippi. Nat Cell Biol 4(2) 95-105... 

Goldberg YP, Nicholson DW, Rasper DM, Kalchman MA, Koide HB, Graham RK, Bronun M, Kazemi-Esfarjani P, Thornberry NA, Vaillancourt JP, Hayden MR (1996) Qeavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nat Genet 13(4) 442-449... 

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