LUBAC: a new player in polyglucosan body disease

Abstract

Altered protein ubiquitination is associated with the pathobiology of numerous diseases; however, its involvement in glycogen metabolism and associated polyglucosan body (PB) disease has not been investigated in depth. In PB disease, excessively long and less branched glycogen chains (polyglucosan bodies, PBs) are formed, which precipitate in different tissues causing myopathy, cardiomyopathy and/or neurodegeneration. Linear ubiquitin chain assembly complex (LUBAC) is a multi-protein complex composed of two E3 ubiquitin ligases HOIL-1L and HOIP and an adaptor protein SHARPIN. Together they are responsible for M1-linked ubiquitination of substrates primarily related to immune signaling and cell death pathways. Consequently, severe immunodeficiency is a hallmark of many LUBAC deficient patients. Remarkably, all HOIL-1L deficient patients exhibit accumulation of PBs in different organs especially skeletal and cardiac muscle resulting in myopathy and cardiomyopathy with heart failure. This emphasizes LUBAC's important role in glycogen metabolism. To date, neither a glycogen metabolism-related LUBAC substrate nor the molecular mechanism are known. Hence, current reviews on LUBAC's involvement in glycogen metabolism are lacking. Here, we aim to fill this gap by describing LUBAC's involvement in PB disease. We present a comprehensive review of LUBAC structure, its role in M1-linked and other types of atypical ubiquitination, PB pathology in human patients and findings in new mouse models to study the disease. We conclude the review with recent drug developments and near-future gene-based therapeutic approaches to treat LUBAC related PB disease.

AAV-Mediated Artificial miRNA Reduces Pathogenic Polyglucosan Bodies and Neuroinflammation in Adult Polyglucosan Body and Lafora Disease Mouse Models

“…In any event, the abnormal glycogen in these diseases all but certainly has overextended branches driving it to precipitation, and glycogen synthase downregulation should mitigate the problem as in LD and APBD. In fact, our recent results already confirm this for RBCK1 deficiency [ 53 , 54 ]. An important point to note is that the present GYS1 downregulating therapy or others are expected to slow or halt PB formation but not remove existing ones.…”

Pathomorphogenesis of Glycogen-Ground Glass Hepatocytic Inclusions (Polyglucosan Bodies) in Children after Liver Transplantation

“…This, however, is not sufficient to suggest variations in the treatment, as the main purpose of clinical transplants is to save the graft rather than preventing transient, non-progressive histological changes. Likewise, while it seems reasonable to try to alleviate the irreversible permanent PG storage in secondary glycogen storage disease (SGSD) by using molecules that bind to the lysosomal membrane protein (LAMP-1) [ 26 ] in order to enhance autophagic glycogen catabolism [ 27 ], this would not be recommended for a non-progressive and reversible lesion such as drug-induced GGG.…”