My broad research interest lies in understanding the molecular basis of human genetic diseases and developing therapeutics for their treatment. Specifically, my research primarily focuses on neuromuscular diseases, which are those that affect muscle, the nerves that innervate muscle or the neuromuscular junction, which is the connection between the two. One way to approach this problem is to study mutations that disrupt normal neural development. Proximal spinal muscular atrophy (SMA) is a prime example. After cystic fibrosis, SMA is the most common autosomal recessive childhood disease. The disease affects 1/10,000 live born children. It is characterized by degeneration of the a-motor neurons in the spinal cord, which causes proximal, symmetrical limb and trunk muscle weakness that progresses to paralysis and ultimately death. Currently, there is no available treatment for SMA patients.
Mutations in survival motor neuron 1 (SMN1) gene are responsible for SMA. In humans, two virtually identical copies of SMN are present, SMN1 and SMN2. SMN1 produces only full-length transcripts (FL-SMN) and is therefore the SMA-determining gene, whereas the predominant transcript from SMN2 is an exon 7 alternatively spliced form. The SMN2 gene also produces a low level of FL-SMN transcript, which explains why SMA is not embryonic lethal in humans. Nevertheless, lower motor neurons eventually succumb to the reduced SMN dosage and degenerate. Why motor neurons are specifically affected is not clear but it has been proposed that this may be due to a distinct role for SMN in this cell type.
We have developed a translational research program for SMA. The research is multi-faceted and uses biochemistry, cell biology, molecular biology, and animal modeling. We use these approaches to decipher SMN function within nerve and muscle, the two tissues affected in SMA. We have also generated a hypomorphic allelic series of Smn mutations in mice that mimic human SMN2 splicing. This provides us with a classical approach to study Smn function in vivo and determine the biochemical mechanism of motor neuron death in SMA. These animals are also to be used to determine their potential for pre-clerical testing of treatment modalities.
POST-DOCTORAL POSITIONS ARE AVAILABLE.
Heier C.R., DiDonato C.J. (2009) Translational readthrough by the aminoglycoside geneticin (G418) modulates SMN stability in vitro and improves motor function in SMA mice in vivo. Hum Mol Genet: Vol 18, No 7: 1310-1322.
Gavrilina T.O., McGovern V.L., Workman E., Crawford T.O., Gogliotti R.G., DiDonato C.J., Monani U.R., Morris G.E., Burghes A.H. (2008) Neuronal SMN expression corrects spinal muscular atrophy in severe SMA mice while muscle-specific SMN expression has no phenotypic effect. Hum Mol Genet Apr 15;17(8): 1063-75.
Heier C.R., Gogliotti R.G., DiDonato C.J. (2007) SMN transcript stability: could modulation of messenger RNA degradation provide a novel therapy for spinal muscular atrophy? J Child Neurol Aug; 22(8): 1013-8.
Schmid A., DiDonato C.J. (2007) Animal models of spinal muscular atrophy. J Child Neurol. Aug; 22(8): 1004-12.