For its correct development and function, nervous tissue synthesizes various key components but is also reliant on essential nutrients. Choline is one of such nutrients that is necessary for the synthesis of phospholipids and the generation of the neurotransmitter acetylcholine. A novel disorder was recently identified and shown to be caused by mutations on SLC44A1, the gene that encodes the choline transporter-like protein 1. With an early childhood-onset presentation, this novel leukoencephalopathy is characterized by severe white matter involvement, optic nerve atrophy, ataxia, dysarthria, tremors, and patients have delayed motor and speech development. In order to have a valid animal model for the disorder, we generated the first Slc44a1 mutant mice to characterize the underlying pathology and disease mechanisms caused by a defect in choline transport. Using the Slc44a1 mutants, we will determine how choline dysregulation impairs oligodendrocyte differentiation, myelination, and neuron function. Our aims are to:

• Determine the neuropathology caused by impaired choline transport
• Establish the proteomic and metabolic changes caused by choline deficiency
• Evaluate the therapeutic potential of choline supplementation

Combined, this project addresses several unmet scientific and medical needs that are set to have a significant beneficial impact on scientific and societal communities.

Project financed by ELA up to: 81 000 €