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Reduction of RPT6/S8 (a Proteasome Component) and Proteasome Activity in the Cortex is Associated with Cognitive Impairment in Lewy Body Dementia.

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Alghamdi, Amani 
Vallortigara, Julie 
Howlett, David R 
Broadstock, Martin 
Hortobágyi, Tibor 


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.



Alzheimer’s disease, Parkinson’s disease with dementia, RPT6, amyloid-beta, cognitive impairment, dementia with Lewy bodies, tau, ubiquitin proteasome system, ATPases Associated with Diverse Cellular Activities, Aged, Aged, 80 and over, Analysis of Variance, Cerebral Cortex, Cognitive Dysfunction, Cohort Studies, Female, Humans, Lewy Body Disease, Male, Mental Status and Dementia Tests, Proteasome Endopeptidase Complex

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J Alzheimers Dis

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IOS Press
The main funding was provided by a PhD studentship from King Saud University College of Science (A.A.), with additional support from the Alzheimer’s Society UK and the BUPA Foundation. Dr Broadstock was an Edmond and Lily Safra Senior Research Fellow. The research in Newcastle was supported in part by the Dunhill Medical Trust (R173/1110). Tissue for this study was provided by (i) the Newcastle Brain Tissue Resource; (ii) the London Neurodegenerative Brain Bank; and (iii) the Thomas Willis Oxford Brain Collection. All three resources are funded in part by grants from the UK Medical Research Council and by Brains for Dementia Research, a joint venture between Alzheimer’s Society and Alzheimer’s Research UK. Professor Margaret Esiri and Drs. Olaf Ansorge, Safa Al-Sarraj, Istvan Bodi, and Andrew King are thanked for neuropathological diagnosis of cases. Dr. Claire Troakes at the MRC London Neurodegenerative Diseases Brain Bank is thanked for supplying tissue sections. The authors express their thanks to all the donors and brain banks for the tissue used in this study. This Newcastle Brain Tissue Resource is supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Unit based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University and the Medical Research Council and Brains for Dementia Research. The MRC London Neurodegenerative Diseases Brain Bank is funded by the Medical Research Council and Brains for Dementia Research. TH has received salary support from the Hungarian Brain Research Programme Grant No. KTIA 13 NAP-AII/7. CB would like to thank the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and [Institute of psychiatry] King’s College London. This article presents independent research supported/funded by the National Institute for Health Research (NIHR).