Assessing neurodegeneration in Pompe disease using a degeneration-specific neurofilament light chain (NF-L) antibody

Pompe disease (PD) is an autosomal recessive disorder in which mutations in the acid-alpha glucosidase ( Gaa ) gene result in impaired or absent GAA protein. Since GAA acts to degrade lysosomal glycogen, the impact is widespread glycogen accumulation. Neuronal glycogen accumulation is prominent and autopsy case reports and animal model data indicate that neurodegeneration occurs as the disease progresses. We recently described an antibody, MCA-6H63, that uniquely binds to a portion of NF-L during degeneration (PMID: 37091583). Here we tested the hypothesis that MCA-6H63 could be used to immunohistochemically identify degenerating neurons in PD. First, we evaluated the spinal cord of a human with late-onset PD who succumbed to cardiorespiratory failure at age 54. Positive staining was noted in the soma of neurons in the ventral horn of the spinal cord, fibers in the ventral roots, and in white matter tracts. However, in control experiments in which tissue was incubated in control IgG mouse antibody, staining was absent. We next evaluated the brainstem and spinal cord in the Gaa -/- mouse model of PD (age 10-12 mo). Positive MCA-6H63 staining was noted in the soma of neurons in the medulla and extensive labeling of white matter tracts. In the spinal cord, we observed sparse labeling of neuronal fibers, presumably dendrites. Lastly, we examined a unique mouse model (age 10-12 mo) with Gaa absent only in choline acetyltransferase (ChAT) positive neurons (ChAT-cre +/+ ▪Gaa +/- ▪eYFP +/+ ▪Flox-Gaa +/+ ). MCA-6H63 staining was also observed in distinct brainstem nuclei and in some white matter tracts. We conclude that MCA-6H63 staining in mouse and human CNS tissue verifies neurodegeneration in PD. Since axons contain more NF-L than perikaryon, future studies with MCA-6H63 in PD or other neurodegenerative conditions should focus on neural fibers (e.g., ventral root, peripheral nerve axons) as this may provide a useful surrogate tag for neuronal degeneration. Collectively, the data support the thesis that effective PD treatment strategies must ultimately mitigate neurodegeneration. Funding: R01HD052682 (DDF and BJB); 1K99NS133388-01A1(SR) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.