Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodies

• DOI: 10.1016/j.nbd.2005.11.005
• Publication Date: 2005-12-28T15:03:58Z
• Authors: Marta Barrachina; Esther Castaño; Esther Dalfó; Tamara Maes; Carlos Buesa; Isidro Ferrer
• Keywords: Lewy Body Disease; Male; 0301 basic medicine; Proteasome Endopeptidase Complex; Parkinson's disease; Down-Regulation; Neurosciences. Biological psychiatry. Neuropsychiatry; 03 medical and health sciences; α-synuclein; Alzheimer Disease; Humans; Dementia with Lewy Bodies; RNA, Messenger; Aged; Aged, 80 and over; Cerebral Cortex; Neurons; Medulla Oblongata; UCHL; Proteasome; Brain; A-synuclein; Parkinson Disease; Middle Aged; 3. Good health; Substantia Nigra; Protein Subunits; Female; Lewy Bodies; RC321-571; Signal Transduction

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.