Polyglutamine diseases

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]. 

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

Shimohata T, Onodera O, Tsuji S (2000) Interaction of expanded polyglutamine stretches with nuclear transcription factors leads to aberrant transcriptional regulation in polyglutamine diseases. Neuropathology 20(4) 326-333... 

Huntington s disease (HD) is caused by mutations in a gene called Huntingtin. The disease is caused by abnormal expansion of CAG repeats, which encode long stretches of glutamine (polyglutamine). In addition to HD, there are several other known polyglutamine diseases such as spinocerebellar ataxia, and spinal and bulbar muscular atrophy. " ... 

Based on the results from various studies described above, it is clear that the failure of the ubiquitin-proteasome pathway ultimately contributes to cell death or degeneration in polyglutamine diseases. This process is probably progressive. Initial formation of aggregates with proteins with long polyglutamine stretches perhaps impairs proteasome activity, which in turn leads to accumulation of more protein aggregates, and thus misfolded proteins could build up in the cell. Initially, however, impairment of the proteasome probably has an effect on synaptic properties of the neuron because as discussed elsewhere in this chapter, proteasome activity in various subcellular compartments of the neuron is essential for normal synaptic function and plasticity. 

Luthi-Carter R, Hanson SA, Strand AD, Bergstrom DA, Chun W, Peters NL, et al. Dysregulation of gene expression in the R6/2 model of polyglutamine disease Parallel changes in muscle and brain. Hum Mol Genet 2002 11(17) 1911-1926. 

Bauer PO, Nukina N (2009) The pathogenic mechanisms of polyglutamine diseases and current therapeutic strategies. J Neurochem 110 1737-1765... 

Evert BO, Wuhner U, Klockgether T (2000) Ceh death in polyglutamine diseases. Ceh Tissue Res 301 189-204. 

Hughes RE (2002) Polyglutamine disease acetyltransferases awry. Curr Biol 12(4) R141-R143... 

Taylor JP et al (2003) Aberrant histone acetylation, altered transcription, and retinal degeneration in a Drosophila model of polyglutamine disease are rescued by CREB-binding protein. Genes Dev 17(12) 1463-1468... 

Tsuji S (2004) Spinocerebellar ataxia type 17 latest membs of polyglutamine disease group highlights unanswered questions. Arch Neurol 61 183-184... 

Naigai Y, Fujikake N, Popiel HA, Wada K (2010) Induction of molecular chaperones as a therapeutic strategy for the polyglutamine diseases. Curr Pharm Biotechnol Fab 16 [Epub tihead of print]... 

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