| 20S core particle (CP) | The proteolytic chamber containing β1 (caspase-like), β2 (trypsin-like), and β5 (chymotrypsin-like) subunits |
| 19S regulatory particle (RP) | Recognizes ubiquitinated substrates, removes the ubiquitin chain, and translocates substrates into the 20S CP |
| Aβ-mediated inhibition | Aβ oligomers directly impair proteasome activity by altering the composition of the 19S regulatory particle, reducing substrate recognition and deubiquitination capacity[@tseng2018] |
| Tau-mediated inhibition | Paired helical filament (PHF)-tau directly inhibits proteasome activity in AD brain tissue, with inhibition correlating with disease severity[@keck2003] |
| Oxidative stress | Elevated ROS further impairs proteasome function |
| Impaired clearance | Reduced expression of proteasome activators (PA28, PA700) in AD brains |
| Genetic risk factors | PARKIN (E3 ubiquitin ligase) and PINK1 mutations impair mitochondrial quality control and reduce ubiquitin-dependent degradation |
| LRRK2 toxicity | LRRK2 mutations (G2019S) cause proteasome inhibition through kinase-dependent mechanisms[@cookson2015] |
| FBXO7 dysfunction | Mutations in FBXO7 impair proteasome function and mitophagy[@durcan2014] |
| Alpha-synuclein toxicity | Oligomeric α-synuclein directly inhibits proteasome activity |
| Lewy body pathology | Ubiquitinated α-synuclein inclusions indicate failed proteasomal clearance |
| TDP-43 pathology | Ubiquitinated TDP-43 inclusions are present in 95% of ALS cases (except SOD1 familial)[@arai2006][@neumann2006] |
| Databases | OMIMOrphanetClinicalTrialsPubMed |
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