New published paper: a step forward for Lysosomal Storage Disorders


In the last years, the Advanced Cell Models Laboratory at iBET and ITQB NOVA, has been focused in developing human cellular models to study the dysfunction of brain cells in disease states. In the work recently published in Scientific Reports, the group applied a 3D neural cell model to study a rare lysosomal storage disease called Mucopolysaccharidosis type VII (MPS VII) and results may now help to better understand the molecular basis for MPS VII brain anomalies, for which currently there is little understanding. Ultimately, the study can help to identify new therapeutic approaches for this disease.

Lysosomal storage disorders (LSD) are inherited metabolic diseases caused by deficient activity of enzymes which role is to digest unwanted macromolecules, both from inside and outside cells, in lysosomes (organelles found in animal cells, that can break down many kinds of biomolecules). Mutations in genes that code for those enzymes leads to lysosomal dysfunction, and so to the accumulation of toxic materials inside cells. Among the 70 LSD known, that affect about 1:8000 born child, is Mucopolysaccharidosis type VII.

MPS VII is caused by deficient activity of β-glucuronidase (β-gluc), an enzyme found in lysosomes of all nucleated mammalian cells responsible for the degradation of glycosaminoglycans (GAGs). GAGs are one of the main components of the extracellular matrix and so deficient β-gluc activity leads to GAGs accumulation in many tissues, including the brain, causing a range of neurological features expressed in several levels of defective cognitive capacity. Due to the complexity of this disease, its molecular basis is still poorly understood making disease prognosis and treatment challenging.

iBET/ITQB researchers have shown previously that their 3D neural cell models differentiated from human induced pluripotent stem cells (hiPSC), called neurospheroids, there is deposition of extracellular matrix and the presence of different molecules outside the cells that can mimic more accurately the brain microenvironment than other models proposed so far (Simão et al., 2018, Stem Cell Reports). In the study now published, the team, coordinated by Catarina Brito, applied the neurospheroid model to hiPSC generated from cells of a MPS VII patient, creating the first human 3D neural cell model of a lysosomal storage disease. Importantly, they showed that the model reproduces the major molecular hallmarks of the disease, including GAGs accumulation, and some of the neural defects observed in the brains of the MPS VII patients, not observed in other types of models. Specifically, they found reduced neuronal activity and altered functionality of the neuronal network in MPS VII patient-derived neurospheroids.

This work provides a new human experimental model for identifying the molecular mechanisms underlying MPSVII-associated neurological dysfunction, elucidating the bases of the cognitive defects associated with several lysosomal storage diseases and opening new avenues for the identification of therapeutic targets.