Combined proteomic and lipidomic studies in Pompe disease allow a better disease mechanism understanding

Abstract

Pompe disease (PD) is caused by deficiency of the enzyme acid α‐glucosidase resulting in glycogen accumulation in lysosomes. Clinical symptoms include skeletal myopathy, respiratory failure, and cardiac hypertrophy. We studied plasma proteomic and lipidomic profiles in 12 PD patients compared to age‐matched controls. The proteomic profiles were analyzed by nLC‐MS/MS SWATH method. Wide‐targeted lipidomic analysis was performed by LC‐IMS/MS, allowing to quantify >1100 lipid species, spanning 13 classes. Significant differences were found for 16 proteins, with four showing the most relevant changes (GPLD1, PON1, LDHB, PKM). Lipidomic analysis showed elevated levels of three phosphatidylcholines and of the free fatty acid 22:4, and reduced levels of six lysophosphatidylcholines. Up‐regulated glycolytic enzymes (LDHB and PKM) are involved in autophagy and glycogen metabolism, while down‐regulated PON1 and GPLD1 combined with lipidomic data indicate an abnormal phospholipid metabolism. Reduced GPLD1 and dysregulation of lipids with acyl‐chains characteristic of GPI‐anchor structure suggest the potential involvement of GPI‐anchor system in PD. Results of proteomic analysis displayed the involvement of multiple cellular functions affecting inflammatory, immune and antioxidant responses, autophagy, Ca2+‐homeostasis, and cell adhesion. The combined multi‐omic approach revealed new biosignatures in PD, providing novel insights in disease pathophysiology with potential future clinical application.

An Alloy Platform of Dual‐Fingerprints for High‐Performance Stroke Screening

“…The multiplexed profiling in serum, like untargeted multi‐omics based on liquid/gas‐phase MS techniques, has been extensively studied for precision disease diagnosis. [ 31 ] These techniques need to combine different sample treatment protocols (e.g., protein precipitation, desalting, digestion, and chromatography separation), leading to a low analysis throughput of ≈hours per sample and a large volume of ≈10 to 500 µL per workflow. By comparison, the advantages of our approach could be mainly concluded into two aspects: 1) every single apparatus in the multiplexed platform enjoys a fast response time (≈second per sample) for high‐throughput detection; 2) the sampling and analysis process for LDI‐MS and SERS are easy‐operation and highly compatible with each other.…”

Muscle Proteomic Profile before and after Enzyme Replacement Therapy in Late-Onset Pompe Disease

“…To precisely decipher the effects of ERT on muscle tissue, proteomic analyses have been adopted based both on our experience in proteomics of skeletal muscle from patients and healthy subjects under various conditions [26][27][28][29][30][31][32], and on literature reports [33,34]. More specifically, a double proteomic approach has been applied based on two-dimensional difference gel electrophoresis (2D-DIGE) and label-free liquid chromatography-mass spec-trometry (LC-MS/MS) analyses to determine both differential abundance of intact proteoforms and of trypsin digested proteins in muscle extracts of LOPD patients before and after 12 months of ERT.…”

The role of GPLD1 in chronic diseases

“…Carcinoembryonic antigen (CEA) is one of the most extensively used clinical tumor markers (Agrawal et al, 2020; Farahani et al, 2020; Grunnet & Sorensen, 2012; Sidorina et al, 2021), which is upregulated in advanced colorectal cancer by approximately 90% (Yamamoto et al, 2005). CEA is attached to the surface of cell membrane via GPI anchor, thus the membrane‐bound CEA can be cleaved by GPLD1 (Bramswig et al, 2013).…”

“…Pompe disease (PD), also named as glycogen storage disease type II, is caused by the lack or deficiency of the lysosomal enzyme acid a-glucosidase, thereby resulting in severe cardiac and skeletal muscle myopathy or respiratory failure due to the progressive accumulation of glycogen (Meena & Raben, 2020). One of the studies has demonstrated that decreased GPLD1 level is significantly associated with the lipids disorders with acyl-chain characteristics of GPI-anchor structure in PD patients, suggesting the potential involvement of GPI-anchor system in PD (Sidorina et al, 2021).…”