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 (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.
de Pril
Remko
R
Graduate School Neurosciences Amsterdam, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands.
Fischer
David F
DF
van Leeuwen
Fred W
FW
D000255:Adenosine Triphosphate; D000367:Age Factors; D000818:Animals; D002449:Cell Aggregation / Q000502:physiology; D016923:Cell Death; D006801:Humans; D009422:Nervous System Diseases / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*
C479419:UBB protein, human; D025801:Ubiquitin; D000255:Adenosine Triphosphate; D046988:Proteasome Endopeptidase Complex