Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodies
Barrachina, Marta (Hospital Universitari de Bellvitge)
Castaño, Esther (Universitat de Barcelona)
Dalfo, Esther (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Maes, Tamara (Parc Científic de Barcelona. Oryzon Genomics)
Buesa, Carlos (Universitat de Barcelona. Departament de Bioquímica i Biologia Molecular)
Ferrer, Isidro (Universitat de Barcelona. Unitat de Neuropatologia Experimental)

Data:	2006
Resum:	Parkinson disease (PD) and dementia with Lewy bodies (DLB) are characterized by the accumulation of abnormal α-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 a-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 agematched 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 11Sα. 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.
Drets:	Tots els drets reservats.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Dementia with Lewy Bodies ; Parkinson's disease ; UCHL ; Proteasome ; A-synuclein
Publicat a:	Neurobiology of disease, Vol. 22, Num. 2 (2006) , p. 265-73, ISSN 0969-9961

DOI: 10.1016/j.nbd.2005.11.005

9 p, 525.8 KB

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