title: Accumulation of α-synuclein in dementia with Lewy bodies is associated with decline in the α-synuclein-degrading enzymes kallikrein-6 and calpain-1.
abstract: Kallikrein-6 and calpain-1 are amongst a small group of proteases that degrade α-synuclein. We have explored the possibility that reduction in the level or activity of these enzymes contributes to the accumulation of α-synuclein in Lewy body diseases. We measured calpain-1 activity by fluorogenic activity assay, kallikrein-6 level by sandwich ELISA, and levels of α-synuclein and α-synuclein phosphorylated at serine 129 (α-synuclein-P129), in post-mortem brain tissue in pure dementia with Lewy bodies (DLB, n=12), Alzheimer's disease (AD, n=20) and age-matched controls (n=19). Calpain-1 activity was significantly reduced in DLB within the cingulate and parahippocampal cortex, regions with highest α-synuclein and α-synuclein-P129 load, and correlated inversely with the levels of α-synuclein and α-synuclein-P129. Calpain-1 was unaltered in the thalamus and frontal cortex, regions with less α-synuclein pathology. Kallikrein-6 level was reduced in the cingulate cortex in the DLB cohort, and correlated inversely with α-synuclein and α-synuclein-P129. Kallikrein-6 was also reduced in DLB in the thalamus but not in relation to α-synuclein or α-synuclein-P129 load and was unaltered in the frontal and parahippocampal cortex. In SH-SY5Y cells overexpressing wild-type α-synuclein there was partial co-localisation of kallikrein-6 and calpain-1 with α-synuclein, and siRNA-mediated knock-down of kallikrein-6 and calpain-1 increased the amount of α-synuclein in cell lysates. Our results indicate that reductions in kallikrein-6 and calpain-1 may contribute to the accumulation of α-synuclein in DLB.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Miners
authors.forename: Ruth
authors.initials: R
authors.lastname: Renfrew
authors.forename: Marta
authors.initials: M
authors.lastname: Swirski
authors.forename: Seth
authors.initials: S
authors.lastname: Love
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002154:Calpain / Q000378:metabolism*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007610:Kallikreins / Q000378:metabolism*; D020961:Lewy Body Disease / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D009447:Neuroblastoma / Q000473:pathology; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D051844:alpha-Synuclein; D012694:Serine; C103551:KLK6 protein, human; D007610:Kallikreins; D002154:Calpain; C484806:CAPN1 protein, human