Free sialic storage diseases are rare genetic lysosomal diseases in the leukodystrophy family. The most severe, infantile forms lead to death before the age of 2 years. Salla disease, a more moderate form, is characterized by severe cognitive and motor deficits. There are also intermediate forms. These lysosomal storage diseases have been little studied, due to their very low frequency apart from certain isolates such as the Salla region in Finland. However, recently, it appeared that this pathology suffered from underdiagnoses caused by a lack of knowledge of the symptoms and a lack of systematic testing to detect it. Moreover, its distribution in the world has been found to be more generalized. This discovery aroused renewed interest in this pathology. In particular, a consortium of researchers has been created around a foundation of families of patients (STAR) in the USA.

Team A is interested in the lysosome, a cellular organelle whose roles are to eliminate and recycle “cellular waste” by breaking it down into small molecules, and to participate in cellular nutrition. It focuses mainly on the lysosomal transporters that enable small molecules to be evacuated. Since the early 2000s, part of the team has been studying sialin, the lysosomal transporter of a sugar, sialic acid, whose mutations (defects) can cause disease. In 2004, a publication made it possible to study its activity in the lysosome, as well as that of pathological mutants, a study continued in 2008. Subsequently, the team turned its attention to the search for molecules to understand the mechanisms involved, but also to pave the way for pharmacological treatment. This treatment was based on the idea that, for the most common mutation causing Salla disease, the sialin protein remained partially capable of fulfilling its role when present in the lysosome, but was only partially sent to the lysosome. This is probably due to a problem of “shape”, the folding of sialin that prevents its recognition by the cellular systems that guide proteins to their areas of function. The idea was therefore to look for small molecules that would help sialin take the right shape to be recognized. The first interesting compounds were described in 2012, and the first compound aimed at correcting the pathology in 2020 in collaboration with team B. However, while this compound provided proof of principle that the so-called “pharmacological chaperone” method could work to redirect sialin to the lysosome, it did not actually treat the pathology. This is due to its mode of action: it binds tightly to sialin at the same point as the sugar which sialin must remove from the lysosome; this sugar can no longer be taken up by sialin and accumulates instead of being removed.

The aim of this project is therefore to develop second-generation chaperone molecules. These molecules will target the misfolded sialin region without preventing sugar binding and transport. We have begun to build models of sialin and to understand the structural consequences of the “Salla” mutation. Based on these models, we will screen in silico very large databases of molecules (some of some already used in therapy). This virtual screening has the advantage of being very rapid in identifying the types of molecules that can help folding by “repairing” the structure destabilized by the mutation. As soon as a promising compound is identified, it will immediately be tested on cells to verify that it has the expected chaperone effect and enables sialin to be active. In a second phase, its effect will be evaluated on patient cells, showing that it can correct the accumulation of harmful sialic acid causing the pathology.

Project financed by ELA up to: 97 000 €

Project financed by ELA up to: 97 900 €

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 €