CIM6P/IGF‐2 Receptor Ligands Reverse Deficits in Angelman Syndrome Model Mice

Abstract

Angelman syndrome (AS), a genetic disorder that primarily affects the nervous system, is characterized by delayed development, intellectual disability, severe speech impairment, and problems with movement and balance (ataxia). Most affected children also have recurrent seizures (epilepsy). No existing therapies are capable of comprehensively treating the deficits in AS; hence, there is an urgent need to identify new treatments. Here we show that insulin‐like growth factor 2 (IGF‐2) and mannose‐6‐phosphate (M6P), ligands of two independent binding sites of the cation‐independent M6P/IGF‐2 receptor (CIM6P/IGF‐2R), reverse most major deficits of AS modeled in mice. Subcutaneous injection of IGF‐2 or M6P in mice modeling AS restored cognitive impairments as assessed by measurements of contextual and recognition memories, motor deficits assessed by rotarod and hindlimb clasping, and working memory/flexibility measured by Y‐maze. IGF‐2 also corrected deficits in marble burying and significantly attenuated acoustically induced seizures. An observational battery of tests confirmed that neither ligand changed basic functions including physical characteristics, general behavioral responses, and sensory reflexes, indicating that they are relatively safe. Our data provide strong preclinical evidence that targeting CIM6P/IGF‐2R is a promising approach for developing novel therapeutics for AS. Lay Summary There is no effective treatment for the neurodevelopmental disorder Angelman syndrome (AS). Using a validated AS mouse model, the Ube3am−/p+, in this study we show that systemic administration of ligands of the cation independent mannose‐6‐phosphate receptor, also known as insulin‐like growth factor 2 receptor (CIM6P/IGF‐2R) reverses cognitive impairment, motor deficits, as well as seizures associated with AS. Thus, ligands that activate the CIM6P/IGF‐2R may represent novel, potential therapeutic targets for AS.

Insulin-Like Growth Factor 2 As a Possible Neuroprotective Agent and Memory Enhancer—Its Comparative Expression, Processing and Signaling in Mammalian CNS

“…Experiments on rodents with artificial increase of systemic or local IGF-2 concentration, that was achieved either by an injection of the recombinant protein or by ectopic gene expression, demonstrated that IGF-2 may alleviate cognitive deficits in animal models of AD [ 20 ], ASD [ 111 ], Angelman syndrome [ 247 ], Fragile X syndrome [ 101 ], as well as aging-related cognitive decline [ 108 ].…”

“…It was shown in a number of studies [ 11 , 111 ] that memory-enhancing action of IGF-2 is mediated primarily via IGF2R. Later it was demonstrated that activation of IGF2R by its another ligand, m6p, leads to similar effects [ 165 , 247 ]. Moreover, IGF2R is most likely responsible for clearance of protein aggregates in some neurodegenerative disorders [ 20 , 49 ].…”

“…Importantly, in the same study it was demonstrated that another IGF2R ligand—m6p—when injected in the same manner as IGF-2 (in the hippocampus in rat or systemically in mouse), has the same effects as IGF-2. IGF-2 and m6p were also found to be interchangeable for IGF2R-mediated effects in reversing the cognitive impairment in the model of Angelman syndrome [ 247 ].…”

“…Recently, it was shown that another endogenous ligand of IGF2R, m6p, may induce effects identical to those of IGF-2 [ 165 , 247 ]. M6p tag is attached to many lysosomal enzymes and there is some data that these enzymes may undergo Ca 2+ -dependent exocytosis in rat hippocampal pyramidal neurons [ 264 ].…”

“…In the Angelman syndrome mouse model, Ube3 am-/p+ , systemic administration of IGF-2 significantly attenuated acoustically induced seizures and restored cognitive impairments assessed by measurements of contextual and recognition memories, motor deficits and working memory [ 247 ]. In a mouse model of autism spectrum disorders (ASD), BTBR T + Itpr3 tf /J strain, IGF-2 injection reversed the cellular abnormalities associated with protein overproduction: activation of the AMPK-mTOR-S6K pathway, increased translation in synapses and decreased autophagy level [ 111 ].…”