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Selective knockout of acid α‐glucosidase GAA gene expression in the medulla alters breathing (1091.3)
Author(s) -
Fuller David,
Elmallah Mai Kamal,
Ross Heather,
Cerreta Anthony,
Corti Manuela,
Smith Barb,
Poirier Amy,
Mandel Ronald,
Byrne Barry
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1091.3
Subject(s) - respiratory system , ventilation (architecture) , medullary cavity , hypercapnia , neuropathology , control of respiration , endocrinology , knockout mouse , hypoxic ventilatory response , medicine , biology , respiratory center , neuroscience , disease , receptor , mechanical engineering , engineering
Pompe disease results from gene mutations in GAA ‐ an enzyme necessary to degrade lysosomal glycogen. Hypoventilation is a hallmark feature historically attributed to Pompe‐associated muscle pathology but the contribution of brain to this deficit is unclear. In ongoing experiments, we are using a Cre‐Lox recombination approach to knockout (KO) the GAA gene in medullary respiratory neurons while leaving somatic muscle expression unaltered. AAV vectors driving Cre recombinase were injected into the ventrolateral medulla of C57Bl/6 mice in which exons 4‐8 of the GAA gene were floxed with loxP sites. Whole body plethysmography was used to assess breathing patterns at 1‐2 months post‐injection during baseline (21% O 2 ) and respiratory challenge (7% CO 2 , 21% O 2 ). During baseline conditions at 2 months, AAV‐Cre injected mice had increased ventilation compared to saline injected mice (P<0.05). However, during respiratory challenge at 2 months, the AAV‐Cre group had a reduced ventilatory response (P<0.05). These preliminary results demonstrate that medullary GAA KO can alter breathing. Our working hypothesis is that neuronal glycogen accumulation leads to dysfunction in medullary networks, and the increased baseline breathing indicates a compensatory response to ongoing neuropathology. The blunted hypercapnic ventilatory response may reflect an inability to fully compensate for the ongoing neuropathology. Grant Funding Source : Funding: Parker B. Francis Fellowship (MKE), 1R21NS081431‐01 (DDF, BJB)