Glycogen pileup in the distal airway cells of Pompe disease (PD) may contribute to respiratory impairments in patients with the disease, a new study published in the FASEB Journal found.

PD is a disorder in the glycogen hydrolyzation within the lysosomes due to alpha-glucosidase (GAA) deficiency. The disease includes skeletal, nervous, cardiac, and respiratory manifestations. Respiratory insufficiency is a common outcome of PD due to muscle, motor neurons, and airway smooth muscle impairment.

The authors state that both types of distal airway cells depend on correct lysosomal functioning for performing their functions. Alveolar type 1 cells use lysosomes for gas-exchange purposes, whereas alveolar type 2 (AT2) cells use them for surfactant production. Therefore, it would seem reasonable to think that GAA deficiency could impair these cells, further contributing to overall respiratory malfunction in patients with PD.


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A mouse model of PD without GAA was developed and compared to a wild-type mouse in several aspects, including lung histology with periodic acid-Schiff staining, quantification of immunohistochemistry staining, pulmonary function, and electron microscopy. The authors also conducted a single cell-RNA seq on the distal airways of the PD mouse model.

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They found engorged lamellar bodies indicating lysosomal glycogen accumulation in the PD mouse model only. “AT2 positive surfactant protein-C (SPC) staining and lysosomal positive lysosomal associated membrane protein 1 (LAMP1) staining is more evident with increased colocalization of LAMP1 with the type 2 cell marker after quantification of each marker in Gaa−/− airway cells,” they said.

The PD mouse model demonstrated a substantial reduction in total and central airway resistance and increased lung compliance compared to wild-type mice. The authors also found lung tissue elastic changes consistent with typical PD respiratory modifications.

The authors suggest that this novel finding of the distal airway cells’ involvement in respiratory disease can contribute to treatment development by directly addressing this pathophysiology.

“GAA enzyme deficiency leads to glycogen accumulation in the distal airway stem cells that may contribute to respiratory impairments in Pompe disease,” the authors concluded.

Reference

El Haddad L, Lai E, Murthy P, Tata P, ElMallah M. GAA deficiency disrupts distal airway cells in Pompe diseaseFASEB J. Published online May 13, 2022. doi:10.1096/fasebj.2022.36.s1.l7829