title: Reduction of RPT6/S8 (a Proteasome Component) and Proteasome Activity in the Cortex is Associated with Cognitive Impairment in Lewy Body Dementia.
abstract: Lewy body dementia is the second most common neurodegenerative dementia and is pathologically characterized by α-synuclein positive cytoplasmic inclusions, with varying amounts of amyloid-β (Aβ) and hyperphosphorylated tau (tau) aggregates in addition to synaptic loss. A dysfunctional ubiquitin proteasome system (UPS), the major proteolytic pathway responsible for the clearance of short lived proteins, may be a mediating factor of disease progression and of the development of α-synuclein aggregates. In the present study, protein expression of a key component of the UPS, the RPT6 subunit of the 19S regulatory complex was determined. Furthermore, the main proteolytic-like (chymotrypsin- and PGPH-) activities have also been analyzed. The middle frontal (Brodmann, BA9), inferior parietal (BA40), and anterior cingulate (BA24) gyrus' cortex were selected as regions of interest from Parkinson's disease dementia (PDD, n = 31), dementia with Lewy bodies (DLB, n = 44), Alzheimer's disease (AD, n = 16), and control (n = 24) brains. Clinical and pathological data available included the MMSE score. DLB, PDD, and AD were characterized by significant reductions of RPT6 (one-way ANOVA, p < 0.001; Bonferroni post hoc test) in prefrontal cortex and parietal cortex compared with controls. Strong associations were observed between RPT6 levels in prefrontal, parietal cortex, and anterior cingulate gyrus and cognitive impairment (p = 0.001, p = 0.001, and p = 0.008, respectively). These findings highlight the involvement of the UPS in Lewy body dementia and indicate that targeting the UPS may have the potential to slow down or reduce the progression of cognitive impairment in DLB and PDD.
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, London, UK.|Department of Biochemistry, King Saud University, College of Science, Riyadh, Saudi Arabia.
authors.forename: Amani
authors.initials: A
authors.lastname: Alghamdi
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, London, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Vallortigara
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, London, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Howlett
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, London, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Broadstock
authors.affiliation: Department of Neuropathology, Institute of Pathology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Hortobágyi
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, London, UK.|University of Exeter Medical School, University of Exeter, Devon, UK.
authors.forename: Clive
authors.initials: C
authors.lastname: Ballard
authors.affiliation: NIHR Biomedical Research Centre for Mental Health, South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Kings College London, UK.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Thomas
authors.affiliation: Department of Psychiatry, University of Cambridge, UK.
authors.forename: John T
authors.initials: JT
authors.lastname: O'Brien
authors.affiliation: Department of Neurobiology, Ward Sciences and Society, Karolinska Institute, Stockholm Sweden.|Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
authors.forename: Dag
authors.initials: D
authors.lastname: Aarsland
authors.affiliation: Institute of Neuroscience and Newcastle University Institute for Ageing, Campus for Ageing and Vitality, UK.
authors.forename: Johannes
authors.initials: J
authors.lastname: Attems
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, London, UK.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Francis
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, London, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Whitfield
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D060825:Cognitive Dysfunction / Q000378:metabolism* / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D020961:Lewy Body Disease / Q000378:metabolism* / Q000473:pathology; D008297:Male; D000073216:Mental Status and Dementia Tests; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*
chemical_list: C092282:PSMC5 protein, human; D046988:Proteasome Endopeptidase Complex; D000074183:ATPases Associated with Diverse Cellular Activities
keywords: Alzheimer’s disease; Parkinson’s disease with dementia; RPT6; amyloid-beta; cognitive impairment; dementia with Lewy bodies; tau; ubiquitin proteasome system