期刊
AUTISM RESEARCH
卷 14, 期 1, 页码 29-45出版社
WILEY
DOI: 10.1002/aur.2418
关键词
Angelman syndrome; Ube3a; insulin‐ like growth factor 2; mannose‐ 6‐ phosphate; insulin‐ like growth factor 2 receptor; cation‐ independent mannose‐ 6‐ phosphate receptor; memory; motor response; mouse model; audiogenic seizure
资金
- Foundation for Angelman Syndrome Therapeutics (FAST)
- NIH [MH065635, T32MH019524, T32AG052909]
- Canadian Institutes of Health Research [F31MH116585]
This study demonstrates that ligands activating the CIM6P/IGF-2R can reverse cognitive impairment, motor deficits, and seizures associated with AS in a validated mouse model. Therefore, these ligands may serve as novel therapeutic targets for AS.
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 Ube3a(m-/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.
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