Alleviation of a polyglucosan storage disorder by enhancement of autophagic glycogen catabolism.

This work employs adult polyglucosan body disease (APBD) models to explore the efficacy and mechanism of action of the polyglucosan-reducing compound 144DG11. APBD is a glycogen storage disorder (GSD) caused by glycogen branching enzyme (GBE) deficiency causing accumulation of poorly branched glycogen inclusions called polyglucosans. 144DG11 improved survival and motor parameters in a GBE knockin (Gbeys/ys ) APBD mouse model. 144DG11 reduced polyglucosan and glycogen in brain, liver, heart, and peripheral nerve. Indirect calorimetry experiments revealed that 144DG11 increases carbohydrate burn at the expense of fat burn, suggesting metabolic mobilization of pathogenic polyglucosan. At the cellular level, 144DG11 increased glycolytic, mitochondrial, and total ATP production. The molecular target of 144DG11 is the lysosomal membrane protein LAMP1, whose interaction with the compound, similar to LAMP1 knockdown, enhanced autolysosomal degradation of glycogen and lysosomal acidification. 144DG11 also enhanced mitochondrial activity and modulated lysosomal features as revealed by bioenergetic, image-based phenotyping and proteomics analyses. As an effective lysosomal targeting therapy in a GSD model, 144DG11 could be developed into a safe and efficacious glycogen and lysosomal storage disease therapy.

Clustered miRNAs and their role in biological functions and diseases.

MicroRNAs (miRNAs) are endogenous, small non-coding RNAs known to regulate expression of protein-coding genes. A large proportion of miRNAs are highly conserved, localized as clusters in the genome, transcribed together from physically adjacent miRNAs and show similar expression profiles. Since a single miRNA can target multiple genes and miRNA clusters contain multiple miRNAs, it is important to understand their regulation, effects and various biological functions. Like protein-coding genes, miRNA clusters are also regulated by genetic and epigenetic events. These clusters can potentially regulate every aspect of cellular function including growth, proliferation, differentiation, development, metabolism, infection, immunity, cell death, organellar biogenesis, messenger signalling, DNA repair and self-renewal, among others. Dysregulation of miRNA clusters leading to altered biological functions is key to the pathogenesis of many diseases including carcinogenesis. Here, we review recent advances in miRNA cluster research and discuss their regulation and biological functions in pathological conditions.