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.

至少有五种酶（包括三种 E3 泛素连接酶）专用于糖原的球形结构。如果没有任何糖原，糖原就会恢复到类似于植物界支链淀粉的结构。这种支链淀粉病（多聚葡聚糖体形成）会导致致命的神经系统疾病，包括由于糖原分支酶缺乏而导致的成人多聚葡聚糖体病（APBD）、由于拉福林糖原磷酸酶或马林E3泛素连接酶和1型多聚葡聚糖体缺乏而导致的拉福拉病（LD）由于 RBCK1 E3 泛素连接酶缺乏而导致的肌病 (PGBM1)。人们对这些酶在糖原结构中的功能知之甚少。为了了解这些功能，我们对 APBD、LD 和 PGBM1 的支链淀粉病进行了小鼠比较研究。我们发现，在骨骼肌中，聚葡聚糖体形成两种主要类型，小型且众多（“卵石”）或巨大且单一（“巨石”），这主要取决于它们形成的肌纤维类型，“卵石”糖酵解中的“”和氧化纤维中的“巨石”。这种模式概括了大脑中已知的 LD、星形胶质细胞中的无数尘埃状和神经元中的单个巨大尺寸。我们还表明，氧化肌纤维相对免受支链淀粉病的影响，部分是通过高度增加的糖原分支酶表达来实现的。我们提出了聚葡聚糖体大小依赖性细胞坏死的证据。我们表明，性别在基因型、大脑区域和肌纤维类型特异性方面影响支链淀粉病。 RBCK1 是线性泛素链组装复合体 (LUBAC) 的一个组成部分，这是唯一已知的头尾线性泛素化细胞机制，对许多细胞途径至关重要。我们表明，RBCK1 缺陷的支链淀粉病并不是由于线性泛素化的丧失，并且 RBCK1 或 LUBAC 的另一个功能必须存在并在糖原的形成中发挥作用。这项工作为理解对神经和神经肌肉功能和疾病至关重要的哺乳动物碳水化合物储存库的结构决定因素开辟了多种新途径。