Human models of neurological lysosomal storage disorders

Lysosomal storage disorders (LSDs) are a group of rare diseases caused by mutations in genes coding for lysosomal enzymes or proteins, leading to accumulation of undegraded substrates, dysfunction of the lysosome, and consequent cellular and organ damage. Around 70% of these diseases present with neurological affectation, in many cases as severe and early-onset neurodegeneration, for which there is no available treatment. Our group is focused on neuronopathic Gaucher disease, Sanfilippo syndrome type C, and Niemann-Pick type C, all of them presenting severe neuropathology and caused by dysfunction in the metabolism of a different molecule for each disease. To date, most studies have examined late neuronal defects in animal models, however, all these molecules play essential roles during brain development, and considering the higher degree of complexity of the human brain, there is a need to investigate early disease mechanisms in different human brain cells to better understand disease mechanisms, identify new therapeutic targets, and develop novel therapeutic approaches. To address these questions, we are developing novel in vitro human models of these different LSDs by combining human induced pluripotent stem cells (hiPSCs) with genome editing and differentiation protocols towards different brain cells as well as brain organoids. We later examine these human models using different biochemical, imaging, transcriptomics, and functional assays to identify molecular and cellular alterations. Additionally, we will test different therapeutic approaches using these human models, with focus on genome editing techniques.

These disorders are very representative of the more than 50 known LSDs in which different types of molecules accumulate. These three disorders represent accumulation of glycosphingolipids (Gaucher disease), of polysaccharides (Sanfilippo syndrome), and of cholesterol (Niemann-Pick). Moreover, LSDs have some commonalities with age-related neuropathologies such as Parkinson’s disease, Alzheimer disease, and Frontotemporal dementia, in which dysfunction of the lysosome is one of the main hallmarks. Therefore, a better understanding on LSDs can have an impact on our understanding of these other diseases.