Aggregate-selective removal of pathological tau by clustering-activated degraders.

Autor: Benn J; UK Dementia Research Institute at the University of Cambridge, Cambridge CB2 0AH, UK., Cheng S; UK Dementia Research Institute at the University of Cambridge, Cambridge CB2 0AH, UK., Keeling S; UK Dementia Research Institute at the University of Cambridge, Cambridge CB2 0AH, UK., Smith AE; UK Dementia Research Institute at the University of Cambridge, Cambridge CB2 0AH, UK., Vaysburd MJ; MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK., Böken D; UK Dementia Research Institute at the University of Cambridge, Cambridge CB2 0AH, UK., Miller LVC; MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK., Katsinelos T; UK Dementia Research Institute at the University of Cambridge, Cambridge CB2 0AH, UK.; MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK., Franco C; MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK., Dupré E; CNRS EMR9002-BSI-Integrative Structural Biology, LabEx DISTALZ, F-59000 Lille, France.; Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE, Risk Factors and Molecular Determinants of Aging-Related Diseases, F-59000 Lille, France., Danis C; CNRS EMR9002-BSI-Integrative Structural Biology, LabEx DISTALZ, F-59000 Lille, France.; Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE, Risk Factors and Molecular Determinants of Aging-Related Diseases, F-59000 Lille, France.; Université Lille, Inserm, CHU Lille, Lille Neuroscience & Cognition, LabEx DISTALZ, F-59000 Lille, France., Landrieu I; CNRS EMR9002-BSI-Integrative Structural Biology, LabEx DISTALZ, F-59000 Lille, France.; Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE, Risk Factors and Molecular Determinants of Aging-Related Diseases, F-59000 Lille, France., Buée L; Université Lille, Inserm, CHU Lille, Lille Neuroscience & Cognition, LabEx DISTALZ, F-59000 Lille, France., Klenerman D; UK Dementia Research Institute at the University of Cambridge, Cambridge CB2 0AH, UK., James LC; MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK., McEwan WA; UK Dementia Research Institute at the University of Cambridge, Cambridge CB2 0AH, UK.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2024 Aug 30; Vol. 385 (6712), pp. 1009-1016. Date of Electronic Publication: 2024 Aug 29.
DOI: 10.1126/science.adp5186
Abstrakt: Selective degradation of pathological protein aggregates while sparing monomeric forms is of major therapeutic interest. The E3 ligase tripartite motif-containing protein 21 (TRIM21) degrades antibody-bound proteins in an assembly state-specific manner due to the requirement of TRIM21 RING domain clustering for activation, yet effective targeting of intracellular assemblies remains challenging. Here, we fused the RING domain of TRIM21 to a target-specific nanobody to create intracellularly expressed constructs capable of selectively degrading assembled proteins. We evaluated this approach against green fluorescent protein-tagged histone 2B (H2B-GFP) and tau, a protein that undergoes pathological aggregation in Alzheimer's and other neurodegenerative diseases. RING-nanobody degraders prevented or reversed tau aggregation in culture and in vivo, with minimal impact on monomeric tau. This approach may have therapeutic potential for the many disorders driven by intracellular protein aggregation.
Databáze: MEDLINE
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