Park, H. I. | bioRxiv Science

bioRxiv2026

Mucin-binding protein shuttles enable delivery of brain-targeted therapeutics

The blood-brain barrier (BBB) poses a major obstacle to the delivery of therapeutics into the central nervous system (CNS) due to its highly restrictive permeability. Here, we introduce glycan-targeted delivery vehicles, or GlycoShuttles, that traverse the BBB by harnessing the cerebrovascular glycocalyx, a carbohydrate-rich layer lining the BBB lumen. We discover that mucin-domain glycoproteins within this structure serve as novel entry portals for brain delivery and engineer mucin-binding protein shuttles that enable efficient transport of diverse molecular cargo across the BBB into multiple key brain cell types. This modular platform facilitates enhanced brain delivery of a variety of payloads, including antibodies and lysosomal proteins, and demonstrates therapeutic efficacy in mouse models of dementia. Our findings establish mucin-targeted GlycoShuttles as a versatile platform for noninvasive brain delivery of therapeutics, opening new avenues for the treatment of CNS diseases.

neuroscience↗

bioRxiv2025

Ubiquitin-specific protease 20 promotes CCCP-induced mitophagy through deubiquitination and stabilization of serine/threonine protein kinase PINK1

While Parkinsons disease (PD) is predominantly sporadic, various mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been linked to the autosomal recessive form of PD. PINK1, a serine/threonine protein kinase, holds a pivotal role in mitophagy - a process that selectively eliminates damaged mitochondria, overseeing mitochondrial quality control and ultimately safeguarding against neuronal cell loss in PD. Understanding the regulation of PINK1 stability is essential in comprehending PD pathology, given its involvement in a pro-survival pathway. Although some components of the ubiquitin-proteasome system (UPS) are recognized for mediating the proteolysis of PINK1, the specific enzyme(s) responsible for positively influencing PINK1 stability have remained elusive. In this study, we demonstrated that ubiquitin-specific protease 20 (USP20) functions as a novel deubiquitinating enzyme targeting PINK1. We found that USP20 positively regulates PINK1 levels by hydrolyzing Lys 48-linked polyubiquitin chains, promoting mitophagy under the treatment of mitochondrial depolarizing agent carbonyl cyanide m-chlorophenyl hydrazine (CCCP). Furthermore, CCCP treatment accelerates the deubiquitinating activity of USP20, facilitating the degradation of impaired mitochondria and enhancing mitochondrial quality control via PINK1 accumulation. Taken together, these findings unveil a novel enzyme, USP20, positively impacting PINK1 level and promoting CCCP-induced mitophagy. In addition, this study establishes a comprehensive map depicting how PINK1 can be regulated both positively and negatively through the coordinated action of multiple members in the UPS.

cell biology↗