A new study led by the Sapkota Lab, in collaboration with Johnson & Johnson Neuroscience Discovery, has demonstrated that targeted protein degradation can selectively eliminate endogenous α-synuclein and suppress its pathological aggregation.
The study, led by Sapkota Lab PhD student Bill Carton, is now published in npj Parkinson’s Disease.
The researchers used the Affinity-directed PROtein Missile (AdPROM) platform, pioneered by the Sapkota Lab, combining the VHL E3 ubiquitin ligase substrate receptor with an α-synuclein-selective nanobody to direct α-synuclein for degradation by the proteasome.
The approach produced robust and selective degradation of endogenous α-synuclein across human cell models. Importantly, depletion of α-synuclein also reduced pre-formed fibril (PFF)-induced aggregation in primary neurons expressing human α-synuclein, providing evidence that reducing the cellular pool of α-synuclein can interfere with the formation of pathological aggregates.
The study further demonstrated nanobody-guided degradation of several disease-associated α-synuclein variants.
These findings highlight targeted protein degradation as a potential strategy for directly addressing α-synuclein accumulation, a central pathological feature of Parkinson’s disease and related synucleinopathies.
Professor Sapkota, who led the study, said: “This study provides proof-of-concept that targeted degradation of α-synuclein can suppress its aggregation, which is a key disease-associated process. More work is needed to establish whether we can use this approach to degrade α-synuclein and pathological aggregates in the brains of rodent models of Parkinson’s disease, and whether this can ultimately be translated into an effective therapeutic strategy.”
He added: “It was a pleasure to work closely with such outstanding colleagues at Johnson & Johnson Neuroscience Discovery. This collaboration is a wonderful example of what can be achieved through a strong and productive partnership between academia and industry.”
“This work illustrates the enormous value of collaborating with industry partners such as Johnson & Johnson. These partnerships help the MRC PPU translate fundamental discoveries into greater real-world impact, while providing our PhD students and postdoctoral researchers with exceptional training and development opportunities.”
Professor Dario Alessi, Director, MRC Protein Phosphorylation and Ubiquitylation Unit
The study was a collaborative effort involving Géraldine Gelders, Joke Van Elsen, Louis De Muynck, Arjan Buist and Diederik Moechars from Johnson & Johnson Neuroscience Discovery, and Gajanan Sathe, Jin-Feng Zhao, Nur M. Kocaturk, Sascha Roth and Thomas J. Macartney from the Sapkota Lab.
Bill Carton was supported by a PhD studentship from the Cunningham Trust, while the project also received funding from the Government of Belgium to support the collaboration between the Sapkota Lab and Johnson & Johnson Neuroscience Discovery.