Transcriptome assessment of the Pompe (Gaa-/-) mouse spinal cord indicates widespread neuropathology.
Pompe disease, caused by deficiency of acid alpha-glucosidase (GAA), leads to widespread glycogen accumulation and profound neuromuscular impairments. There has been controversy, however, regarding the role of central nervous system pathology in Pompe motor dysfunction. We hypothesized that absence of GAA protein causes progressive activation of neuropathological signaling, including pathways associated with cell death. To test this hypothesis, genomic data (Affymetrix Mouse Gene Array 2.0ST) from the midcervical spinal cord in 6 and 16 mo old Pompe (Gaa-/-) mice were evaluated (Broad Institute Molecular Signature Database), along with spinal cord histology. The midcervical cord was selected because it contains phrenic motoneurons, and phrenic-diaphragm dysfunction is prominent in Pompe disease. Several clinically important themes for the neurologic etiology of Pompe disease emerged from this unbiased genomic assessment. First, pathways associated with cell death were strongly upregulated as Gaa-/-mice aged, and motoneuron apoptosis was histologically verified. Second, proinflammatory signaling was dramatically upregulated in the Gaa-/-spinal cord. Third, many signal transduction pathways in the Gaa-/-cervical cord were altered in a manner suggestive of impaired synaptic function. Notably, glutamatergic signaling pathways were downregulated, as were "synaptic plasticity pathways" including genes related to neuroplasticity. Fourth, many genes and pathways related to cellular metabolism are dysregulated. Collectively, the data unequivocally confirm that systemic absence of GAA induces a complex neuropathological cascade in the spinal cord. Most importantly, the results indicate that Pompe is a neurodegenerative condition, and this underscores the need for early therapeutic intervention capable of targeting the central nervous system.
Department of Physical Therapy, College of Public Health and Health Professions, University of Florida, Gainesville, Florida.|McKnight Brain Institute, University of Florida, Gainesville, Florida.|Center for Respiratory Research and Rehabilitation, University of Florida, Gainesville, Florida.
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SMF
Turner
Center for Respiratory Research and Rehabilitation, University of Florida, Gainesville, Florida.|Department of Pediatrics, Divisions of Cellular and Molecular Therapy and Pediatric Cardiology, College of Medicine, University of Florida, Gainesville, Florida; and.|Powell Gene Therapy Center, University of Florida, Gainesville, Florida.
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DJ
Falk
Center for Respiratory Research and Rehabilitation, University of Florida, Gainesville, Florida.|Department of Pediatrics, Divisions of Cellular and Molecular Therapy and Pediatric Cardiology, College of Medicine, University of Florida, Gainesville, Florida; and.|Powell Gene Therapy Center, University of Florida, Gainesville, Florida.
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BJ
Byrne
Department of Physical Therapy, College of Public Health and Health Professions, University of Florida, Gainesville, Florida; ddf@phhp.ufl.edu.|McKnight Brain Institute, University of Florida, Gainesville, Florida.|Center for Respiratory Research and Rehabilitation, University of Florida, Gainesville, Florida.
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Fuller
D000818:Animals; D016923:Cell Death; D002574:Cervical Vertebrae / Q000473:pathology; D020869:Gene Expression Profiling; D006003:Glycogen / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D007249:Inflammation / Q000473:pathology; D051379:Mice; D009410:Nerve Degeneration / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013116:Spinal Cord / Q000473:pathology*; D059467:Transcriptome / Q000235:genetics*; D000520:alpha-Glucosidases / Q000172:deficiency* / Q000378:metabolism
D012333:RNA, Messenger; D006003:Glycogen; D000520:alpha-Glucosidases
Pompe; cervical; neurodegeneration; neuroinflammation; plasticity