title: Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodies.
abstract: Parkinson disease (PD) and dementia with Lewy bodies (DLB) are characterized by the accumulation of abnormal alpha-synuclein and ubiquitin in protein aggregates conforming Lewy bodies and Lewy neurites. Ubiquitin C-terminal hydrolase-1 (UCHL-1) disassembles polyubiquitin chains to increase the availability of free monomeric ubiquitin to the ubiquitin proteasome system (UPS) thus favoring protein degradation. Since mutations in the UCHL-1 gene, reducing UPS activity by 50%, have been reported in autosomal dominant PD, and UCHL-1 inhibition results in the formation of alpha-synuclein aggregates in mesencephalic cultured neurons, the present study was initiated to test UCHL-1 mRNA and protein levels in post-mortem frontal cortex (area 8) of PD and DLB cases, compared with age-matched controls. TaqMan PCR assays, and Western blots demonstrated down-regulation of UCHL-1 mRNA and UCHL-1 protein in the cerebral cortex in DLB (either in pure forms, not associated with Alzheimer disease: AD, and in common forms, with accompanying AD changes), but not in PD, when compared with age-matched controls. Interestingly, UCHL-1 mRNA and protein expressions were reduced in the medulla oblongata in the same PD cases. Moreover, UCHL-1 protein was decreased in the substantia nigra in cases with Lewy body pathology. UCHL-1 down-regulation was not associated with reduced protein levels of several proteasomal subunits, including 20SX, 20SY, 19S and 11Salpha. Yet UCHL-3 expression was reduced in the cerebral cortex of PD and DLB patients. Together, these observations show reduced UCHL-1 expression as a contributory factor in the abnormal protein aggregation in DLB, and points UCHL-1 as a putative therapeutic target in the treatment of DLB.
authors.affiliation: Institut de Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Barrachina
authors.forename: Esther
authors.initials: E
authors.lastname: Castaño
authors.forename: Esther
authors.initials: E
authors.lastname: Dalfó
authors.forename: Tamara
authors.initials: T
authors.lastname: Maes
authors.forename: Carlos
authors.initials: C
authors.lastname: Buesa
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D001921:Brain / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D002540:Cerebral Cortex / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D015536:Down-Regulation / Q000502:physiology*; D005260:Female; D006801:Humans; D016631:Lewy Bodies / Q000201:enzymology / Q000235:genetics; D020961:Lewy Body Disease / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008526:Medulla Oblongata / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008875:Middle Aged; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013378:Substantia Nigra / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*
chemical_list: D021122:Protein Subunits; D012333:RNA, Messenger; C482860:UCHL1 protein, human; D025801:Ubiquitin; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex