Indiana University-Purdue University Indianapolis (IUPUI) / Pompe disease (PD) is a rare metabolic myopathy characterized by loss of acid alpha-glucosidase (GAA), the enzyme responsible for breaking down glycogen to glucose within the lysosomes. PD cells accumulate massive quantities of glycogen within their lysosomes, and as such, PD is classified as a “lysosomal storage disease” (LSD). GAA-deficient cells also exhibit accumulation of autophagic debris. Symptoms of severe infantile PD include extreme muscle weakness, hypotonia, and hypertrophic cardiomyopathy, resulting in death before one year of age.
Certain LSDs are currently being successfully treated with enzyme replacement therapy (ERT), which involves intravenous infusion of a recombinant enzyme to counteract the endogenous deficiency. ERT has been less successful in PD, however, due to ineffective delivery of the recombinant enzyme. Alternatively, specific genes deletion may reduce lysosomal glycogen load, and could thus be targeted in PD therapy development. Absence of malin (EPM2B) or laforin (EPM2A) has been proposed to impair autophagy, which could reduce lysosomal glycogen levels. Additionally, deficiency of Stbd1 has been postulated to disable lysosomal glycogen import. Furthermore, Ptg deficiency was previously reported to abrogate Lafora body formation and correct neurological abnormalities in Lafora disease mouse models and could have similar effects on PD pathologies.
The goal of this study was to characterize the effects of homozygous disruption of Epm2a, Epm2b, Stbd1, and Ptg loci on total glycogen levels in PD mouse model heart tissue, as in severe infantile PD, it is accumulation of glycogen in the heart that results in fatal hypertrophic cardiomyopathy. Gaa-/- mice were intercrossed with Epm2a-/-, Epm2b-/-, Stbd1-/-, and Ptg-/- mice to generate wildtype (WT), single knockout, and double knockout mice. The results indicated that Gaa-/- hearts accumulated up to 100-fold more glycogen than the WT. These mice also displayed cardiac hypertrophy. However, deficiency of Epm2a, Epm2b, Stbd1, or PTG in the Gaa-/- background did not reveal changes of statistical significance in either heart glycogen or cardiac hypertrophy. Nevertheless, since total glycogen was measured, these deficiencies should not be discarded in future discussions of PD therapy, as increasing sample sizes and/or distinguishing cytosolic from lysosomal glycogen content may yet reveal differences of greater significance.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/7979 |
| Date | 08 1900 |
| Creators | Conway, Betsy Ann |
| Contributors | Roach, Peter J., DePaoli-Roach, Anna, Hurley, Thomas |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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