Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodies
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 availabil...
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doaj-173e45ca6321487eb519d74dd94e841f2021-03-20T04:52:15ZengElsevierNeurobiology of Disease1095-953X2006-05-01222265273Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodiesMarta Barrachina0Esther Castaño1Esther Dalfó2Tamara Maes3Carlos Buesa4Isidro Ferrer5Institut de Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, SpainUnitat de Biología, Campus de Bellvitge, Serveis Cientifico-Tècnics, Universitat de Barcelona, SpainInstitut de Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, SpainORYZON Genomics, Science Park of Barcelona, SpainCell Signaling Group, Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, SpainInstitut de Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Spain; Unitat de Neuropatologia Experimental, Departament de Biologia Cel.lular I Anatomia Patològica, Universitat de Barcelona, Hospitalet de Llobregat, Spain; Corresponding author. Institut de Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, carrer Feixa Llarga sn, 08907 L'Hospitalet de Llobregat, Spain. Fax: +34 93 204 5301.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 α-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 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.http://www.sciencedirect.com/science/article/pii/S0969996105003086Dementia with Lewy BodiesParkinson's diseaseUCHLProteasomeα-synuclein |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Marta Barrachina Esther Castaño Esther Dalfó Tamara Maes Carlos Buesa Isidro Ferrer |
spellingShingle |
Marta Barrachina Esther Castaño Esther Dalfó Tamara Maes Carlos Buesa Isidro Ferrer Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodies Neurobiology of Disease Dementia with Lewy Bodies Parkinson's disease UCHL Proteasome α-synuclein |
author_facet |
Marta Barrachina Esther Castaño Esther Dalfó Tamara Maes Carlos Buesa Isidro Ferrer |
author_sort |
Marta Barrachina |
title |
Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodies |
title_short |
Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodies |
title_full |
Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodies |
title_fullStr |
Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodies |
title_full_unstemmed |
Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodies |
title_sort |
reduced ubiquitin c-terminal hydrolase-1 expression levels in dementia with lewy bodies |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2006-05-01 |
description |
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 α-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 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. |
topic |
Dementia with Lewy Bodies Parkinson's disease UCHL Proteasome α-synuclein |
url |
http://www.sciencedirect.com/science/article/pii/S0969996105003086 |
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