Polyglutamine

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... 

Eight exons of the AR gene encode a protein of around 917 aa depending on two polymorphic regions of polyglutamines (CAG) and polyglycines (GGN) in the N-terminal activation domain. Two isoforms are detected in tissues the predominant (80%) 110 kD (B isoform) and 87 kD (A isoform). It is not clear whether the two isoforms also serve different functions. 

Zhang, Y.-Q. Sarge, K. D. Celastrol inhibits polyglutamine aggregation and toxicity through induction of the heat shock response. J. Mol. Med 2007, 85, 1421-1428. 

Several pathological self-polymerizing systems have been biophysi-cally characterized sufficiently to permit identification of protein or peptide species that could serve as molecular targets in a structure-activity relationship. These include transthyretin (TTR) [73-76], serum amyloid A protein (SAA) [77], microtubule-associated protein tau [78-80], amylin or islet amyloid polypeptide (IAPP) [81,82], IgG light chain amyloidosis (AL) [83-85], polyglutamine diseases [9,86], a-synuclein [47,48] and the Alzheimer s (3 peptide [87-96]. A variety of A(3 peptide assay systems have been established at Parke-Davis to search for inhibitors of fibril formation that could be therapeutically useful [97]. 

Davies SW, Beardsall K, Turmaine M, DiFiglia M, Aronin N, Bates GP. Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions Lancet 1998 351 131-133. 

Kim TW, Tanzi RE. Neuronal intranuclear inclusions in polyglutamine diseases nuclear weapons or nuclear fallout Neuron 1998 21 657-659. 

Koshy BT, Zoghbi HY. The CAG/polyglutamine tract diseases gene products and molecular pathogenesis. Brain Pathol 1997 7 927-942. 

Rubinaztein DC, Wyttenbach A, Rankin J. Intracellular inclusions, pathological markers in diseases caused by expanded polyglutamine tracts J Med Genet 1999 36 265-270. 

Lathrop RH, Casale M, Tobias DJ, Marsh JL, Thompson LM. Modeling protein homopolymeric repeats possible polyglutamine structural motifs for Eluntington s disease. Proc Int Conf Intelligent Syst Molec Biol 1998 6 105-114. 

Altschuler EL, Hud NY, Mazrimas JA, Rupp B. Random coil conformation for extended polyglutamine stretches in aqueous soluble monomeric peptides. J Peptide Res 1997 50 73-75. 

Bates GP, Mangiarini L, Davies SW. Transgenic mice in the study of polyglutamine repeat expansion diseases. Brain Pathol 1998 8 699-714. 

Perez MK, Paulson HL, Pendse SJ, Saionz SJ, Bonini NM, Pittman RN. Recruitment and the role of nuclear localization in polyglutamine-mediated aggregation. J Cell Biol 1998 143 1457-1470. 

Klement IA, Skinner PJ, Kaytor MD, Yi H, Hersch SM, Clark HB, Zoghbi HY, Orr HT. Ataxin-1 nuclear localization and aggregation role in polyglutamine-induced disease in SCA1 transgenic mice [see comments]. Cell 1998 95 41-53. 

Klement IA, Zoghbi HY, Orr HT. Pathogenesis of polyglutamine-induced disease A model for SCA1. Mol Genet Metab 1999 66 172-178. 

Ikeda H, Yamaguchi M, Sugai S, Aze Y, Narumiya S, Kakizuka A. Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nat Genet 1996 13 196-202. 

Polyglutamine repeat 146 unit CAG repeat inserted in hprt gene -... 

Zhuchenko, O., Bailey, J., Bonnen, R et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alA-voltage-dependent calcium channel. Nat Genet. 15 62-69,1997. 

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