Nitschke Silvia, Montalbano Alina P, Whiting Megan E, Smith Brandon H, Mukherjee-Roy Neije, Marchioni Charlotte R, Sullivan Mitchell A, Zhao Xiaochu, Wang Peixiang, Mount Howard, Verma Mayank, Minassian Berge A, Nitschke Felix
Division of Neurology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
EMBO J. 2025 Mar;44(5):1379-1413. doi: 10.1038/s44318-024-00339-3. Epub 2025 Jan 13.
Polyglucosans are glycogen molecules with overlong chains, which are hyperphosphorylated in the neurodegenerative Lafora disease (LD). Brain polyglucosan bodies (PBs) cause fatal neurodegenerative diseases including Lafora disease and adult polyglucosan body disease (ABPD), for which treatments, biomarkers, and good understanding of their pathogenesis are currently missing. Mutations in the genes for the phosphatase laforin or the E3 ubiquitin ligase malin can cause LD. By depleting PTG, an activator of the glycogen chain-elongating enzyme glycogen synthase (GYS1), in laforin- and malin-deficient LD mice, we show that abnormal glycogen chain lengths and not hyperphosphorylation underlie polyglucosan formation, and that polyglucosan bodies induce neuroinflammation. We provide evidence indicating that a small pool of overactive GYS1 contributes to glycogen insolubility in LD and APBD. In contrast to previous findings, metabolomics experiments using in situ-fixed brains reveal only modest metabolic changes in laforin-deficient mice. These changes are not replicated in malin-deficient or APBD mice, and are not normalized in rescued LD mice. Finally, we identify a pool of metabolically volatile malto-oligoglucans as a polyglucosan body- and neuroinflammation-associated brain energy source, and promising candidate biomarkers for LD and APBD, including malto-oligoglucans and the neurodegeneration marker CHI3L1/YKL40.
多聚葡聚糖是具有超长链的糖原分子，在神经退行性疾病拉福拉病（LD）中会发生过度磷酸化。脑多聚葡聚糖体（PBs）会引发致命的神经退行性疾病，包括拉福拉病和成人多聚葡聚糖体病（ABPD），目前针对这些疾病缺乏有效的治疗方法、生物标志物，对其发病机制也缺乏深入了解。磷酸酶拉福林或E3泛素连接酶马林基因的突变可导致LD。通过在缺乏拉福林和马林的LD小鼠中耗尽糖原链延长酶糖原合酶（GYS1）的激活剂PTG，我们发现多聚葡聚糖形成的基础是异常的糖原链长度而非过度磷酸化，并且多聚葡聚糖体会诱导神经炎症。我们提供的证据表明，一小部分过度活跃的GYS1导致了LD和APBD中糖原的不溶性。与之前的研究结果不同，使用原位固定脑进行的代谢组学实验显示，拉福林缺陷小鼠仅出现适度的代谢变化。这些变化在马林缺陷或APBD小鼠中未被复制，在挽救的LD小鼠中也未恢复正常。最后，我们确定了一组代谢不稳定的麦芽寡糖作为与多聚葡聚糖体和神经炎症相关的脑能量来源，以及LD和APBD有前景的候选生物标志物，包括麦芽寡糖和神经退行性标志物CHI3L1/YKL40。
