Triose Phosphate Isomerase Deficiency Is Caused by Altered Dimerization–Not Catalytic Inactivity–of the Mutant Enzymes

Triosephosphate isomerase (TPI) deficiency is an autosomal recessive disorder caused by various mutations in the gene encoding the key glycolytic enzyme TPI. A drastic decrease in TPI activity and an increased level of its substrate, dihydroxyacetone phosphate, have been measured in unpurified cell extracts of affected individuals. These observations allowed concluding that the different mutations in the TPI alleles result in catalytically inactive enzymes. However, despite a high occurrence of TPI null alleles within several human populations, the frequency of this disorder is exceptionally rare. In order to address this apparent discrepancy, we generated a yeast model allowing us to perform comparative in vivo analyses of the enzymatic and functional properties of the different enzyme variants. We discovered that the majority of these variants exhibit no reduced catalytic activity per se. Instead, we observed, the dimerization behavior of TPI is influenced by the particular mutations investigated, and by the use of a potential alternative translation initiation site in the TPI gene. Additionally, we demonstrated that the overexpression of the most frequent TPI variant, Glu104Asp, which displays altered dimerization features, results in diminished endogenous TPI levels in mammalian cells. Thus, our results reveal that enzyme deregulation attributable to aberrant dimerization of TPI, rather than direct catalytic inactivation of the enzyme, underlies the pathogenesis of TPI deficiency. Finally, we discovered that yeast cells expressing a TPI variant exhibiting reduced catalytic activity are more resistant against oxidative stress caused by the thiol-oxidizing reagent diamide. This observed advantage might serve to explain the high allelic frequency of TPI null alleles detected among human populations

Discography in practice: a clinical and historical review

Chronic low back pain is the most common cause of disability in individuals between the ages of 45 and 65. Given the variety of anatomic and pathophysiologic causes of persistent low back pain, it is a difficult diagnosis for clinicians to treat. Discography is a diagnostic option that may link a patient’s subjective complaints of spinal pain to symptomatic disk disease when non-invasive imaging, such as magnetic resonance imaging (MRI), does not find structural abnormalities. A controversial procedure, discography is only necessary to assess painful discs prior to surgical interventions. For accurate discogram interpretation an experienced spine interventionalist must be careful to exclude false positive results and be aware of the patient’s underlying psychological state. This literature review will discuss the following: anatomy and function of the spine and intervertebral disc, intervertebral disc degeneration and discogenic pain, history of discography, indications and contraindications, a description of the procedure, complications, and the current debate regarding its outcomes