Hummer, B. | Search bioRxiv

bioRxiv2024

Identification of novel plasma proteomic biomarkers of Dupuytren Disease

Dupuytren Disease (DD) is a chronic progressive disease that can cause disabling hand deformities. The most common treatments have either high complication rates or high early recurrence rates. Dupuytren lacks a staging biomarker profile to inform the development of preventive therapeutics to improve long-term outcomes. This multi-omic study aimed to create a DD blood proteomic biomarker profile by comparing DD plasma with that of a healthy control group. We measured circulating collagen metabolism peptides and found normal Collagen I synthesis but impaired Collagen I degradation in DD. We measured 6995 serum protein aptamers and identified 68 proteins that showed statistically significant differences compared with the control group. We developed two Diagnostic Proteomic Risk Scores (DPRS) based on hypothesis-free and hypothesis-based analyses. In independent data, our hypothesis-free and hypothesis-based DPRS distinguished Dupuytren from control subjects with accuracies of 76.5% and 70.6%, respectively. Our hypothesis-based DPRS also distinguished DD subjects with different disease progression rates by age at their first corrective procedure (p=0.0018). This pilot study is the first to provide evidence to suggest that Collagen I accumulation in DD results from impaired degradation rather than increased collagen synthesis. It also describes novel DPRS that have potential use as diagnostic and staging biomarker panels for Dupuytren disease.

molecular biology↗

bioRxiv2019

CCDC186 recruits EARP and controls dense-core vesicle cargo sorting by exit

The regulated release of peptide hormones depends on their packaging into dense-core vesicles (DCVs). Two models have been proposed for DCV cargo sorting. The \"sorting by entry\" model proposes that DCV cargos selectively enter nascent DCVs at the trans-Golgi network (TGN). The \"sorting by exit\" model proposes that sorting occurs by the post-TGN removal of non-DCV cargos and retention of mature DCV cargos. Here we show that the coiled-coil protein CCDC186 controls sorting by exit. Ccdc186 KO insulinoma cells secrete less insulin, fail to retain insulin and carboxypeptidase E in mature DCVs at the cell periphery, and fail to remove carboxypeptidase D from immature DCVs. A mutation affecting the endosome-associated recycling protein (EARP) complex causes similar defects in DCV cargo retention and removal. CCDC186 and EARP may act together to control the post-Golgi retention of cargos in mature DCVs.

cell biology↗