Loss of Usp14 results in reduced levels of ubiquitin in ataxia mice.
The ataxia (ax(J)) mutation is a spontaneous recessive mutation that results in reduced expression of ubiquitin-specific protease 14, Usp14. Mice homozygous for the ax(J) mutation are retarded for growth and exhibit several behavioral disorders, including a resting tremor and hindlimb paralysis. Although pathological defects appear to be limited to the central nervous system, reduction of Usp14 expression was widespread in the ax(J) mice. Usp14 co-fractionated with proteasomes isolated from livers and brains of wild-type mice. Proteasomes isolated from the ax(J) brains still possessed deubiquitinating activity and were functionally competent to hydrolyze 20S proteasomal substrates in vitro. However, the levels of monomeric ubiquitin were reduced approximately 35% in most of the ax(J) tissues examined. These results indicate that Usp14 functions to maintain the cellular levels of monomeric ubiquitin in mammalian cells, and that alterations in the levels of ubiquitin may contribute to neurological disease.
Anderson
Christopher
C
Department of Neurobiology, University of Alabama at Birmingham, Civitan International Research Center, Birmingham, Alabama 35294, USA.
Crimmins
Stephen
S
Wilson
Julie A
JA
Korbel
Greg A
GA
Ploegh
Hidde L
HL
Wilson
Scott M
SM
D000818:Animals; D001259:Ataxia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001835:Body Weight; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D009929:Organ Size; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism*
D025801:Ubiquitin; C469268:Usp14 protein, mouse; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex