SLC35A2 loss-of-function variants affect glycomic signatures, neuronal fate and network dynamics

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• SLC35A2 gene variants are linked to developmental brain disorders and epilepsy.
• The functional impact of SLC35A2 variants on brain development and network integrity is not well understood.

Purpose of the Study:

• To investigate the functional consequences of SLC35A2 loss-of-function variants in human neurons.
• To elucidate the impact on brain development, network dynamics, and synaptic function.

Main Methods:

• Utilized an isogenic human induced pluripotent stem cell-derived neuron model.
• Integrated cellular and molecular biology, glycomic analysis, neural network dynamics, and electrophysiology.
• Analyzed neural composition and synaptic activity.

Main Results:

• SLC35A2 variants caused disrupted glycomic signatures and precocious neurodevelopment.
• Neurons exhibited hypoactive, asynchronous network activity due to an inhibitory/excitatory imbalance.
• Preferential differentiation towards GABAergic fate and synaptic changes were observed.

Conclusions:

• Loss of SLC35A2 function impairs human neuron development and network connectivity.
• Findings provide mechanistic insights into SLC35A2-related neurological disorders.
• This study lays groundwork for exploring therapeutic interventions.