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  • Title: Conformational diseases: an umbrella for various neurological disorders with an impaired ubiquitin-proteasome system.
    Author: de Pril R, Fischer DF, van Leeuwen FW.
    Journal: Neurobiol Aging; 2006 Apr; 27(4):515-23. PubMed ID: 16226348.
    Abstract:
    It is increasingly appreciated that failures in the ubiquitin-proteasome system play a pivotal role in the neuropathogenesis of many neurological disorders. This system, involved in protein quality control, should degrade misfolded proteins, but apparently during neuropathogenesis, it is unable to cope with a number of proteins that, by themselves, can consequently accumulate. Ubiquitin is essential for ATP-dependent protein degradation by the proteasome. Ubiquitin+1 (UBB+1) is generated by a dinucleotide deletion (DeltaGU) in UBB mRNA. The aberrant protein has a 19 amino acid extension and has lost the ability to ubiquitinate. Instead of targeting proteins for degradation, it has acquired a dual substrate-inhibitor function; ubiquitinated UBB+1 is a substrate for proteasomal degradation, but can at higher concentrations inhibit, proteasomal degradation. Furthermore, UBB+1 protein accumulates in neurons and glial cells in a disease-specific way, and this event is an indication for proteasomal dysfunction. Many neurological and non-neurological conformational diseases have the accumulation of misfolded proteins and of UBB+1 in common, and this combined accumulation results in the promotion of insoluble protein deposits and neuronal cell death as shown in a cellular model of Huntington's disease.
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