Abstract
At least five enzymes including three E3 ubiquitin ligases are dedicated to glycogen’s spherical structure. Absence of any reverts glycogen to a structure resembling amylopectin of the plant kingdom. This amylopectinosis (polyglucosan body formation) causes fatal neurological diseases including adult polyglucosan body disease (APBD) due to glycogen branching enzyme deficiency, Lafora disease (LD) due to deficiencies of the laforin glycogen phosphatase or the malin E3 ubiquitin ligase and type 1 polyglucosan body myopathy (PGBM1) due to RBCK1 E3 ubiquitin ligase deficiency. Little is known about these enzymes’ functions in glycogen structuring. Toward understanding these functions, we undertake a comparative murine study of the amylopectinoses of APBD, LD and PGBM1. We discover that in skeletal muscle, polyglucosan bodies form as two main types, small and multitudinous (‘pebbles’) or giant and single (‘boulders’), and that this is primarily determined by the myofiber types in which they form, ‘pebbles’ in glycolytic and ‘boulders’ in oxidative fibers. This pattern recapitulates what is known in the brain in LD, innumerable dust-like in astrocytes and single giant sized in neurons. We also show that oxidative myofibers are relatively protected against amylopectinosis, in part through highly increased glycogen branching enzyme expression. We present evidence of polyglucosan body size-dependent cell necrosis. We show that sex influences amylopectinosis in genotype, brain region and myofiber-type-specific fashion. RBCK1 is a component of the linear ubiquitin chain assembly complex (LUBAC), the only known cellular machinery for head-to-tail linear ubiquitination critical to numerous cellular pathways. We show that the amylopectinosis of RBCK1 deficiency is not due to loss of linear ubiquitination, and that another function of RBCK1 or LUBAC must exist and operate in the shaping of glycogen. This work opens multiple new avenues toward understanding the structural determinants of the mammalian carbohydrate reservoir critical to neurologic and neuromuscular function and disease.
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Acknowledgements
We thank UT Southwestern’s Histopathology, Quantitative Light Microscopy (supported by NIH grant P30CA1425431) and Whole Brain Microscopy Cores and Children’s Health’s Electron Microscopy Core, especially Ricardo Olivarez, Marcel Mettlen and Alejandra Vargas.
Funding
The work was funded by NIH grant (P01NS097197 to BM), Japan Society for Promotion of Science KAKENHI grant (22H04988) to KI and UT Southwestern Medical Center Wellstone Cooperative Research Center grant to SM. BM, SM and FN are also supported by Chan-Zuckerberg Initiative Patient-Partnered Collaborations for Rare Neurodegenerative Disease grant (2022-316703).
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Conceptualization: SM, BAM. Investigation: SM, BC, JMS, SN, FN LC, MD, TL, MV, JW, YF. Validation: SM, BAM. Formal analysis: SM, BME, BAM. Resources: KI, FN, BME, BAM. Writing original draft: SM, BAM. Writing, review and editing: SM, BME, BAM. Supervision: SM, BAM. Project administration: BAM. Funding acquisition: SM, KI, BAM.
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Mitra, S., Chen, B., Shelton, J.M. et al. Myofiber-type-dependent ‘boulder’ or ‘multitudinous pebble’ formations across distinct amylopectinoses. Acta Neuropathol 147, 46 (2024). https://doi.org/10.1007/s00401-024-02698-x
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DOI: https://doi.org/10.1007/s00401-024-02698-x