PORTFOLIO

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by loss-of-function mutations of the survival of motor neuron 1 (SMN1) gene, which results in muscle wasting. SMA 1 and SMA 2 are the most severe forms of SMA affecting children at early age while SMA 3 and 4 (also called adult SMA) are milder variants. Clinical interventions for SMA are lacking and patients suffering from SMA 1, 2 or 3 die prematurely. The exact function of the ubiquitously expressed SMN1 and the reason for the selective damage to motor neurons and skeletal muscle in SMA are unclear. In recent years, a role for SMN1 in RNA processing has been described. Similar to SMN1, the peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) protein harbors an RNA-binding domain and interacts with snRNPs. Interestingly, this transcriptional coactivator confers an endurance-trained phenotype in skeletal muscle and ameliorates a number of muscle wasting pathologies with different etiologies, e.g. denervation-induced muscle atrophy, Duchenne muscular dystrophy, sarcopenia, statin-mediated fiber damage or a mitochondrial myopathy.

Our project aims at using novel experimental techniques and bioinformatical approaches to study the functional overlap between SMN1 and PGC-1alpha in skeletal muscle and motor neurons in terms of RNA processing. Second, a better understanding of the pathological changes that cause SMA should be obtained. Finally, we will study whether an increase in PGC-1alpha expression has a therapeutic effect on SMA in disease models and investigate if such an induction of PGC-1alpha gene expression constitutes a potential novel therapeutic avenue to treat SMA patients.

Our project relies on the combination of an experimental part with novel, state-of-the-art bioinformatical techniques that use recently developed methods based on massively parallel sequencing (deep sequencing). The research groups of Prof. Handschin and Prof. Zavolan are thus in a unique position to study SMA with new approaches that hopefully result in breakthroughs in our knowledge of the pathological mechanisms and potential therapeutic approaches to this devastating disease. The “Rare Disease Programme” of the Gebert Rüf Stiftung provides the necessary financial support for such a novel approach.

We have observed a surprisingly strong effect of muscle PGC-1alpha on the morphological and functional stabilization of the neuromuscular junction in adult, differentiated muscle in vivo. This effect, which extends beyond the postsynaptic aspects to the motor neuron, has a big potential to help to improve the interaction between nerve and muscle in diseases with a primary defect in motor neurons such as SMA or amyotrophic lateral sclerosis (ALS). Indeed, experimental evidence in animals now exists that show an ameliorated muscle pathology in such disorders. Thus, based on our results from this project, several new lines of study emerge to bring potential therapies closer to patients. For example, we now investigate how muscle PGC-1alpha promotes a retrograde signal to improve motor neuron function; the identification of the molecular mediators of this cross-talk might provide novel drug targets to specifically stabilize the neuromuscular junction. Moreover, we are currently studying whether our findings indeed transcend the experimental models used in this project and are more generally applicable. The results obtained in this project have finally resulted in follow-up grants of the European Research Council (ERC), the Neuromuscular Research Association Basel (NeRAB), the Swiss Society for Research on Muscle Diseases (SSEM/FSRMM) and SystemsX.ch to further elucidate the systemic impact of PGC-1alpha in muscle health.

Arnold A. S., Gill J., Christe M., Ruiz R., McGuirk S., St-Pierre J., Tabares L., and Handschin C. (2014) “Morphological and functional remodelling of the neuromuscular junction by skeletal muscle PGC-1 .” Nature Commun Apr 1 5:3569, PMID: http://www.ncbi.nlm.nih.gov/pubmed/24686533
Arnold, A. S., Christe, M., and Handschin, C. (2012) «A functional motor unit in the culture dish: co-culture of spinal cord explants and muscle cells.» J Vis Exp Apr 12 (62): 3616, PMID: http://www.ncbi.nlm.nih.gov/pubmed/22525799