Spinal muscular atrophy (SMA) is a neuromuscular disease caused by loss-of-function mutations of
the survival of motor neuron 1 (SMN1) gene. 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 the assembly of small nuclear RNA ribonucleoprotein (snRNP) complexes and in RNA
processing has been described. Similar to SMN1, the peroxisome proliferator-activated receptor γ
coactivator 1α (PGC-1α) 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. We now have preliminary evidence in cultured cells that
PGC-1α also alleviates some of the dysfunctions caused by SMA. Moreover, we have found that
PGC-1α binds to a wide variety of different RNAs indicating a broad role for this protein in RNA
processing. Our project aims at investigating a potential therapeutic effect of PGC-1α on SMA in
cell culture and animal models. In particular, we are interested whether ectopic expression of PGC-
1α can compensate for the loss of SMN1 by restoring normal RNA processing. For this purpose,
we will make use of recently established methods such as photoactivatable ribonucleosideenhanced
crosslinking and immunoprecipitation (PAR-CLIP), deep sequencing of mRNAs
(mRNAseq) and exon-level arrays to obtain a global overview on the involvement of PGC-1α in
RNA binding and processing compared to SMN1. We hope that our approach yields novel insights
into the underlying pathological mechanism of SMA while also revealing novel therapeutic
interventions for this devastating disease.