Conformational diseases: An umbrella for various neurological disorders with an impaired ubiquitin-proteasome system

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 (Delta GU) 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 ail 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. (C) 2005 Elsevier Inc. All rights reserved.