Role of Lysophospholipid Metabolism in Chronic Myelogenous Leukemia Stem Cells

It is well known that mature chronic myelogenous leukemia (CML) cells proliferate in response to oncogenic BCR–ABL1-dependent signaling, but how CML stem cells are able to survive in an oncogene-independent manner and cause disease relapse has long been elusive. Here, I put into the context of the broader literature our recent finding that lysophospholipid metabolism is essential for the maintenance of CML stem cells. I describe the fundamentals of lysophospholipid metabolism and discuss how one of its key enzymes, Glycerophosphodiester Phosphodiesterase Domain Containing 3 (Gdpd3), is responsible for maintaining the unique characteristics of CML stem cells. I also explore how this knowledge may be exploited to devise novel therapies for CML patients.

GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein

A disintegrin and metalloprotease 10 (ADAM10) is the α-secretase for amyloid precursor protein (APP). ADAM10 cleaves APP to generate neuroprotective soluble APPα (sAPPα), which precludes the generation of Aβ, a defining feature of Alzheimer’s disease (AD) pathophysiology. Reduced ADAM10 activity is implicated in AD, but the mechanisms mediating ADAM10 modulation are unclear. We find that the plasma membrane enzyme glycerophosphodiester phosphodiesterase 2 (GDE2) stimulates ADAM10 APP cleavage by shedding and inactivating reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a glycosylphosphatidylinositol (GPI)–anchored inhibitor of ADAM10. In AD, membrane-tethered RECK is highly elevated and GDE2 is abnormally sequestered inside neurons. Genetic ablation of GDE2 phenocopies increased membrane RECK in AD, which is causal for reduced sAPPα, increased Aβ, and synaptic protein loss. RECK reduction restores the balance of APP processing and rescues synaptic protein deficits. These studies identify GDE2 control of RECK surface activity as essential for ADAM10 α-secretase function and physiological APP processing. Moreover, our results suggest the involvement of the GDE2-RECK-ADAM10 pathway in AD pathophysiology and highlight RECK as a potential target for therapeutic development.

Identification of a Glycerophosphocholine Phosphodiesterase, GDE5, in chicken

Glycerophosphodiester phosphodiesterase (GDPD/GDE) catalyzes the hydrolysis of glycerophosphodiesters to glycerol 3-phosphate and alcohol. It was discovered that the glycerophosphodiesterase family plays a role in lipid metabolism and signal pathway in recent years, but little has been known about the characteristics of chicken GDEs. Here, chicken GDE5 (cGDE5) was identified and characterized for the first time. The full length coding cDNA sequence of cGDE5 was cloned, which encoded a polypeptide with 678 amino acids containing a carbohydrate-binding module 20 (CBM20) and a GDPD domain. Tissue expression profiles showed that cGDE5 mRNA was high in various tissues. such as heart, brain, skeletal muscle and testis. Moreover, cGDE5 was demonstrated to exhibit glycerophosphocholine phosphodiesterase activity. These results together suggested that cGDE5, as a unique member of GDE family, may play multiple roles as a cytoplasmic glycerophosphocholine phosphodiesterase.

Glycerophosphodiester Phosphodiesterase Identified as Non-Reliable Serological Marker for Borrelia miyamotoi Disease

The relapsing fever group Borrelia miyamotoi is an emerging tick-borne pathogen. Diagnosis of infection is currently mainly based on serological methods detecting antibodies against B. miyamotoi glycerophosphodiester phosphodiesterase (GlpQ). Here, we scrutinized the reliability of GlpQ as a diagnostic marker and compared the seroprevalence in different study populations and by applying various immunoblotting methods. Antibodies were detected in the sera of 7/53 hunters and in 1/11 sera of Lyme neuroborreliosis patients. Furthermore, 17/74 sera of persons with high concentrations of anti-Borrelia burgdorferi sensu lato (α-Bbsl) antibodies reacted strongly with B. miyamotoi GlpQ in immunoblots. The B. miyamotoi GlpQ seroprevalence was 7/50 in α-Bbsl negative persons. In healthy blood donors from commercial suppliers and from the Austrian Red Cross, seroprevalences were 5/14 and 10/35, respectively. Strikingly, two B. miyamotoi PCR-positive cases from Austria had negative GlpQ serology, indicating poor sensitivity. Finally, when we analyzed sera of dogs, we found α-B. miyamotoi GlpQ antibody seroprevalence in tick-free dogs (n = 10) and in tick-exposed dogs (n = 19) with 2/10 and 8/19, respectively. Thus, our results indicate that GlpQ-based B. miyamotoi serology holds neither specificity nor sensitivity.

Glycerophosphodiester phosphodiesterase 1 (GDE1) acts as a potential tumor suppressor and is a novel therapeutic target for non-mucin-producing colon adenocarcinoma

Colon adenocarcinoma (COAD) represents a major public health issue due to its high incidence and mortality. As different histological subtypes of COAD are related to various survival outcomes and different therapies, finding specific targets and treatments for different subtypes is one of the major demands of individual disease therapy. Interestingly, as these different subtypes show distinct metabolic profiles, it may be possible to find specific targets related to histological typing by targeting COAD metabolism. In this study, the differential expression patterns of metabolism-related genes between COAD (n = 289) and adjacent normal tissue (n = 41) were analyzed by one-way ANOVA. We then used weighted gene co-expression network analysis (WGCNA) to further identify metabolism-related gene connections. To determine the critical genes related to COAD metabolism, we obtained 2,114 significantly differentially expressed genes (DEGs) and 12 modules. Among them, we found the hub module to be significantly associated with histological typing, including non-mucin-producing colon adenocarcinoma and mucin-producing colon adenocarcinoma. Combining survival analysis, we identified glycerophosphodiester phosphodiesterase 1 (GDE1) as the most significant gene associated with histological typing and prognosis. This gene displayed significantly lower expression in COAD compared with normal tissues and was significantly correlated with the prognosis of non-mucin-producing colon adenocarcinoma (p = 0.0017). Taken together, our study showed that GDE1 exhibits considerable potential as a novel therapeutic target for non-mucin-producing colon adenocarcinoma.

Deficiency of the Endocytic ProteinHip1Leads to DecreasedGdpd3expression, Low Phosphocholine, and Kypholordosis

ABSTRACTDeficiency of huntingtin interacting protein 1 (Hip1) results in degenerative phenotypes. Here we generated aHip1deficiency allele where a floxed transcriptional stop-cassette and a humanHIP1cDNA were knocked-in to intron 1 of mouseHip1locus.CMV-Cre-mediated germline excision of the stop-cassette resulted in expression of HIP1 and rescue of theHip1knockout phenotype.Mxl-Cre--mediated excision led to HIP1 expression in spleen, kidney and liver, and also rescued the phenotype. In contrast,GFAP-Cre-mediatedHIP1expression in brain did not rescue the phenotype. Metabolomics and microarrays of severalHip1knockout tissues identified low phosphocholine (PC) levels and lowGlycerophosphodiester Phosphodiesterase Domain Containing 3 (Gdpd3) expression. Since Gdpd3 has lysophospholipase D activity that results in the formation of choline, a precursor of PC,Gdpd3downregulation could lead to the low PC levels. To test ifGdpd3contributes to the Hip1 deficiency phenotype, we generatedGdpd3knockout mice. Double knockout ofGdpd3andHip1worsened the Hip1 phenotype. This suggests that Gdpd3 compensates for Hip1 loss. More detailed knowledge of how Hip1 deficiency leads to low PC will improve our understanding of HIP1 in choline metabolism in normal and disease states.