Jonas van lent, MSc, PhD student/ Supervisor Prof. Dr. Vincent Timmerman, PhD
Peripheral Neuropathy Research Group, University of Antwerp, Belgium
Our lab at the University of Antwerp, Belgium, has a longstanding research interest in the molecular genetics of inherited peripheral neuropathies. Specifically, we aim to gain molecular insights in underlying disease mechanisms of the peripheral nerve. One of our focus is the study of rare genetic mutations causing hereditary sensory and autonomic neuropathy type 1 (HSAN-I).
Ten years ago we discovered HSAN-I associated mutations in the SPTLC2 gene coding for one of the different subunits of the serine palmitoyltransferase (SPT). Note that HSAN-I disease causing mutations were found before in the SPTLC1 gene. From then on, we gained an increasing knowledge in the disease mechanisms of SPTLC1 and SPTLC2 mutations. In HSAN-I, the substrate specificity of the SPT enzyme is altered by mutations in one of both genes. Instead of using the amino acid L-serine, the mutant SPT enzyme now metabolizes L-alanine or L-glycine, causing the formation of neurotoxic products (known as deoxysphingolipids).
Recent clinical studies revealed that L-serine supplementation (providing an excess of L-serine will thereby decrease the relative abundance of L-alanine/L-glycine) improved the neuropathy symptoms of patients due to a reduction of the neurotoxic products. Interestingly, in collaboration with Dr. Guoliang Cui (German Cancer Research Center) we revealed a potential HSAN-I associated immunodeficiency in addition to the neuropathy. Taken together, this finding triggers us to investigate and obtain further molecular insights.
In a new project, we collect blood samples from multiple patients carrying SPTLC1 and SPTLC2 mutations. The blood is used to make induced pluripotent stem cells (iPSCs), which means the “reprogramming” of white blood cells towards a stage they can potentially form any other cell type (besides the placenta or umbilical cord).
We will grow these patient-derived stem cells and develop sensory neurons (these are neurons affected in HSAN-I) by adding small molecules in order to mimic the situation in the human body. Afterwards, we characterize these sensory neurons using advanced microscopy tools and biochemical techniques and compare the findings with neurons derived from iPSCs of healthy control individuals. The formation of neurotoxic lipids will be investigated in collaboration with Dr. Thorsten Hornemann (University Hospital Zurich, Switzerland).
The characterization of these iPSC neurons could result in new insights and explain commonalities between different SPTLC1 and SPTLC2 mutations in the HSAN-I disease mechanisms. Furthermore, our project will allow us to assess the potency of L-serine supplementation in an iPSC sensory neuron culture system and provide a platform for assessing the potential of novel disease-relevant therapeutic targets for HSAN-I.