Polymeric lysosome-targeting chimeras for extracellular α-synuclein degradation in Parkinson's disease.
Polymeric lysosome-targeting chimeras for extracellular α-synuclein degradation in Parkinson's disease.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Delhi, IN · Author affiliation
Department of Pharmacology, Bengal School of Technology, Sugandha, Delhi Road, Near Chuchura Railway Station, Hooghly, 712102, West Bengal, India. abhattacharya031997@gmail.com.Location evidence
Riyadh, SA · Author affiliation
Department of Basic Science, College of Medicine, Princess Nourah Bint Abdulrahman University, P.O.Box 84428, 11671, Riyadh, Saudi Arabia.Location evidence
Jeddah, SA · Author affiliation
Division of Anatomy, Department of Basic Medical Sciences, College of Medicine, University of Jeddah, 23890, Jeddah, Saudi Arabia.Location evidence
Tabuk, SA · Author affiliation
Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, 71491, Tabuk, Saudi Arabia.Location evidence
Kampala, UG · Author affiliation
Department of Biochemistry, Research and Publications, Kampala International University, P.O. Box 20000, Kampala, Uganda. dan4uti@gmail.com.Location evidence
NG · Author affiliation · country only
Department of Biochemistry, Faculty of Basic Medical Sciences, College of Medicine, Federal University of Health Sciences, Otukpo, Benue State, Nigeria. dan4uti@gmail.com.Location evidence
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Original abstract
Disease progression in Parkinson's disease has been driven by extracellular α-synuclein prion-like seeding throughout the course of the disease and therefore not just by the intracellular accumulation of the protein in isolated aggregates. Current therapies utilizing PROTACs cannot address the extra-cellular effects of α-synuclein spreading in this manner. This article proposes PolyTACs (Polymeric Lysosome-Targeting Chimeras) as hybrid antibody-polymer conjugates which use neuronal exofacial thiol groups produced because of DJ-1/GSH dysregulation to capture α-synuclein pathological conformers before they can be derepressed (seeded pathological aggregates) into the cytoplasm. The hybridity of these antibodies (oligomers and fibrils) combined with pyridyl disulfide linkages in the multi-valent polymer allows these compounds to circumvent LTR co-option, and to be trafficked to lysosomes via a non-clathrin pathway. The delivery route for these agents is intended to be via intra-nasal, thereby bypassing many of the issues associated with delivery through the BBB. Delivery to patients will be guided by thiol profiling in cerebrospinal fluid to assist in inclusion-exclusion criteria for patients in prodromal trials. With these developments, it is anticipated that this new class of agent may provide a modular framework adaptable to other proteinopathies such as tau and TDP-43, pending further validation.