Lysosomal deficits in CHD2-related neurodevelopmental disorders

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Autophagy is a dynamic intracellular degradation and recycling pathway. Neurons rely on autophagy to maintain synaptic homeostasis and prevent toxic accumulation of proteins. Lysosomes are at the core of the autophagy pathway. Successful degradation depends on establishing an acidic pH optimum in the lysosome. Impaired autophagy is associated with a variety of diseases, including neurodevelopmental disorders. Haploinsufficiency of CHD2, a chromatin remodeler, has been linked to early onset epileptic encephalopathy. However, molecular mechanisms underpinning CHD2-related neurodevelopmental disorders are still poorly understood. We hypothesized that loss of CHD2 leads to neurodevelopmental disorders due to impaired autophagy. To investigate this, we generated CHD2-deficient human induced pluripotent stem cells and induced neuronal differentiation in vitro. In our human neuronal model of CHD2-deficiency, we identified abnormal perinuclear clustering of lysosomes resembling lysosomal storage disorders, dysregulated lysosomal pH values and correspondingly reduced lysosomal degradative activity. Additionally, we found that CHD2-deficient neurons have a less complex dendritic morphology and a smaller cell soma. Our study establishes a previously unrecognized role of CHD2 in lysosomal function and provides an underlying molecular mechanism of CHD2-related neurodevelopmental disorders.
Faculteit der Sociale Wetenschappen