ArticleMolecular neurodegeneration2023
Targeted degradation of ⍺-synuclein aggregates in Parkinson's disease using the AUTOTAC technology.
Article in Molecular neurodegeneration, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 83 citations in OpenAlex.
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- Engineered autophagy receptors administered with extracellular vesicles eliminate pathological Tau and TDP-43.Nature biomedical engineering · 2026Article
- Synthetic strategies for small molecule compounds for the treatment of Parkinson's disease: targeting α-synuclein.Molecular diversity · 2026Review
- Gaps in the Parkinson's disease therapeutic clinical pipeline: A focus on approaches targeting disease pathobiology.Journal of Parkinson's disease · 2026Review
- Proteasome Dysfunction and Aggregation-Prone Proteins in Neurodegenerative Diseases: From Mechanisms to Therapeutic Opportunities.International journal of molecular sciences · 2026Review
- Associations of DTI-ALPS index and choroid plexus volume with clinical severity across the Parkinson's disease spectrum.NPJ Parkinson's disease · 2026Article
- Molecular engineering of lysosome-based degraders unveils a rapidly expanding therapeutic strategy.Autophagy · 2026Review
- Cell-based regenerative interventions in Parkinson's disease: Overcoming pharmacological limitations.Acta pharmaceutica Sinica. B · 2026Review
- The application of drug delivery systems based on targeted protein degradation chimeras in disease treatment strategies.Journal of nanobiotechnology · 2026Review
- Targeted delivery of glucocerebrosidase to lysosomes: The LYSOTAC (LYSOsome-TArgeting Chimera) technology.Asian journal of pharmaceutical sciences · 2026Article
- Post-translational modifications of selective autophagy receptors: orchestrating cellular homeostasis, disease pathogenesis, and therapeutic opportunities.Cellular & molecular biology letters · 2026Review
- A Degron Decoy System Co-opts Pathological Seeding to Enable Clearance of Multimeric α-Synuclein.bioRxiv : the preprint server for biology · 2026Article
- Targeted Protein Degradation in Cancer: PROTACs, New Targets, and Clinical Mechanisms.Biomolecules · 2026Review
- Propagation of α-synuclein pathology: models, mechanisms and future goals.Molecular neurodegeneration advances · 2026Review
- Breaking the proteasome balance: α-synuclein and the ubiquitin-proteasome system.Frontiers in cell and developmental biology · 2026Review
- Organosulfur Compounds: Potential Therapeutics for Parkinson's Disease.CNS & neurological disorders drug targets · 2026Review
- Mechanistic study on the role of multi-pathway autophagy in ovarian aging: literature review.Apoptosis : an international journal on programmed cell death · 2025Review
- Aggregation and Propagation of α-Synuclein in Parkinson's Disease: A Bibliometric Perspective.Brain and behavior · 2025Article
- Autophagy Dysfunction and Neurodegeneration: Where Does It Go Wrong?Journal of molecular biology · 2025Review
- R406 and its structural analogs reduce SNCA/α-synuclein levels via autophagic degradation.Autophagy · 2025Article
Corrections and comments
- Erratum issued
Authors and funding
15 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundThere are currently no disease-modifying therapeutics for Parkinson's disease (PD). Although extensive efforts were undertaken to develop therapeutic approaches to delay the symptoms of PD, untreated α-synuclein (α-syn) aggregates cause cellular toxicity and stimulate further disease progression. PROTAC (Proteolysis-Targeting Chimera) has drawn attention as a therapeutic modality to target α-syn. However, no PROTACs have yet shown to selectively degrade α-syn aggregates mainly owing to the limited capacity of the proteasome to degrade aggregates, necessitating the development of novel approaches to fundamentally eliminate α-syn aggregates.
methodsWe employed AUTOTAC (Autophagy-Targeting Chimera), a macroautophagy-based targeted protein degradation (TPD) platform developed in our earlier studies. A series of AUTOTAC chemicals was synthesized as chimeras that bind both α-syn aggregates and p62/SQSTM1/Sequestosome-1, an autophagic receptor. The efficacy of Autotacs was evaluated to target α-syn aggregates to phagophores and subsequently lysosomes for hydrolysis via p62-dependent macroautophagy. The target engagement was monitored by oligomerization and localization of p62 and autophagic markers. The therapeutic efficacy to rescue PD symptoms was characterized in cultured cells and mice. The PK/PD (pharmacokinetics/pharmacodynamics) profiles were investigated to develop an oral drug for PD.
resultsATC161 induced selective degradation of α-syn aggregates at DC
conclusionAUTOTAC provides a platform to develop drugs for PD. ATC161, an oral drug with excellent PK/PD profiles, induces selective degradation of α-syn aggregates in vitro and in vivo. We suggest that ATC161 is a disease-modifying drug that degrades the pathogenic cause of PD.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.