What is SMA?
Neuromuscular disease with multi-systemic aspects
Spinal Muscular Atrophy (SMA) is a monogenic neurodegenerative disease affecting motoneurons in the spinal cord and brain stem. Mutations of the Survival of Motoneuron (SMN) gene 1 lead to neurodevelopmental defects and degeneration of the neurons responsible for innvervation of muscles. Due to the lack of the SMN protein in all organs and tissues, SMA is considered now to be a multi-systems disorder.
Besides motoneurons in the central nervous system (CNS), there is growing evidence of an involvement of peripheral organs in SMA. The project SMABEYOND addresses those functions on molecular, cellular and systems levels both in SMA models and patients.
SMABEYOND is an international consortium of laboratories from Spain, United Kingdom, The Netherlands, Italy and Germany and is funded by the European Commission. One aim of the project is to investigate the role of the SMN protein in peripheral organs and determine the intrinsic defects encountered in SMA patients. The ultimate goal is to develop SMA patient-derived disease models and test the therapeutic effect on peripheral organs of systemic SMA therapy (MSCA-ITN-ETN - European Training Network, grant agreement ID: 956185).
SMA is a neurodegenerative disease among others also affecting motoneurons, but also other types of neurons in the nervous system. We use our expertise to develop novel treatment approaches for specific other diseases.
SMATHERIA uses its expertise about dysregulated molecular networks in neurons to unravel mechanisms of viral infections of the nervous system.
Treatments and Therapy
We aim to improve current therapies by novel combinatorial approaches and develop strategies for the treatment of other diseases.
Our other Projects
Identifying novel treatment targets
SMATARGET is a collaborative research project funded by SMA Europe. This working group aims to identify critical hubs in cellular signaling networks in SMA.
Mass spectroscopy screening and other screening techniques enabled us to characterize a network of potentially dysregulated targets in SMA. Those selected targets are screened by the collaborative group of Dr. Elia Di Schiavi (Naples, Italy) for their modulation capacity of motoneuron survival in an nematode C. elegans model for SMA. Selected targets with the highest rescue capacity are further characterized for their molecular function and tested for their capacity as novel combinatorial treatments for SMA.
Dysregulation of the Cytoskeleton
The actin cytoskeleton is a highly dynamic system essential for many functions as cellular integrity, molecular transport, neuronal outgrowth, survival and signaling. With high resolution microscopy, we analyze distinct regulatory patterns of the actin cytoskeleton in different cellular compartments in SMA motoneurons. Therefore, we established an immunocytochemistry-based approach and an automated MatLab-based image quantification pipeline. Furthermore, since connectivity of different motoneurons in the spinal cord is dysregulated as in vitro approaches demonstrate, we further quantify these dysregulations in a 3D spinal cord high resolution imaging setup after whole organ tissue clearing. These complex imaging approaches will elucidate specific neuronal degeneration processes on the molecular level which will help to generate further combinatorial treatment options, not only for SMA.
Stabilizing the SMN Protein
Posttranslational modification, namely phosphorylation of a protein is a multi-facetted mechanism regulating the functions, activity, intracellular distribution, and turnover of a protein. The Survival of Motoneuron (SMN) protein plays central housekeeping roles within different cellular compartments. Moreover, there are additional tissue- and cell-specific functions of SMN. A specific phosphorylation pattern of SMN is mandatory for adequate cellular localization and proper fulfilment of the protein’s functions. However, the stability of this protein decreases when SMN is phosphorylated at a specific amino acid residue leading to further SMN depletion in SMA. To address the diverse roles of SMN phosphorylation, we analyze protein-protein interactions, oligomerization state, and protein stability. Intracellular localization is characterized by immunocytochemical approaches. We further perform high-throughput screening for potential kinases acting on the phosphorylation state of SMN. In this regard, modulation of SMN phosphorylation may be a potential tool acting beneficially in addition to current available SMA therapeutic strategies.
Biomarkers are required for diagnostics, the analysis of disease development and progression. During treatment of patients, the screening of biomarkers can monitor the treatment response and are beneficial for advising and adjusting treatment options. SMATHERIA investigates novel biomarkers in biofluids of SMA patients based on our screening approaches, our proprietary mass spec SMAREACTOME database and mechanistic insights.