Targeted degradation of α-synuclein prevents PFF-induced aggregation
Carton B, Gelders G, Sathe G, Kocaturk NM, Roth S, Macartney TJ, Elsen JV, Muynck LD, Buist A, Moechars D, Sapkota GP
Applications: MSD immunoassay
Reactive species: Human, mouse
"Abstract: Accumulation of misfolded α-synuclein protein in intracellular inclusion bodies of dopaminergic neurons underlies the pathogenesis of Synucleinopathies, which include Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA). Therefore, clearance of misfolded α-synuclein from dopaminergic neurons could in principle offer a therapeutic window for Synucleinopathies, which currently remain untreatable. In this study, we employ the Affinity-directed PROtein Missile (AdPROM) system consisting of the substrate receptor of the CUL2-E3 ligase complex VHL and a nanobody selectively recognising the human α-synuclein protein and demonstrate targeted degradation of endogenous α-synuclein from human cell lines with remarkable selectivity. We further demonstrate that targeted degradation of α-synuclein prevents the pre-formed fibril (PFF)-induced aggregation of α-synuclein in primary neurons derived from rats expressing human α-synuclein. This approach represents the first demonstration of nanobody-guided proteasomal degradation of all clinically relevant α-synuclein variants, highlighting its potential as a therapeutic strategy against Synucleinopathies."
Article snippet: Plates were next washed with 5 × 200 μl of PBS-0.5%Tween-20, and detection antibodies MJFR1 (***), biotinylated D37A6 (***) and 92B (CABT-B1398, 1 mg/ml, Creative Diagnostics) in PBS were added and incubated for 2 hours at room temperature while shaking at 600 rpm. 
Figure 1. Targeted degradation of only human α-synuclein in primary rat cortical neurons as measured by MSD assay.
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