2014 SMA Researcher Meeting Summary: The SMN Protein
We will be posting a series of summaries from our 2014 researcher meeting, highlighting some of the most interesting new developments and discoveries presented there. This is the first of four total updates, and the first of two in basic research.
This summary was written by Cure SMA Scientific Advisory Board member Adrian Krainer PhD, Professor, Cold Spring Harbor Laboratory. Dr. Krainer was also the moderator for this session.
The Survival Motor Neuron Protein: Functions, Binding Partners, and Targets
This session focused on how SMN protein works in cells. This is important because individuals with SMA do not produce SMN protein at high enough levels. Studies were presented on which portions of the SMN protein are important, how SMN is turned on and off, where SMN is located in cells, and what other proteins SMN works with.
Kelsey Gray, from the Matera lab at UNC Chapel Hill, spoke on using the fruit fly as a model system for SMA. Using genetic tools in flies, they tested a series of mutations to the SMN protein. The most severe mutations in flies mapped to part of the SMN protein known as the YG box. The SMN protein works in a complex of proteins, with the complex including multiple copies of the SMN protein itself. Mutations in the YG box prevented the mutant fly SMN protein from binding together or self-associating. Therefore, given the severity of this type of mutation, self-interaction appears to be important for SMN protein function.
Next, Natalia Rodriguez-Muela, from the Rubin lab at Harvard University, spoke on using motor neurons to screen for drug compounds that increase SMN protein levels. They found compounds that regulate SMN protein stability, which refers to the length of time SMN protein exists in cells. Using these same screening methods to increase SMN protein stability, they could improve survival of cultured motor neurons.
Wilfried Rossoll, a past Cure SMA grantee from Emory University, addressed how SMN protein functions in the axon of motor neurons. Motor neurons are the primary cell type affected in SMA. The axon is a long projection that grows out of the spinal cord, to the muscles. The lab used a new assay called trimolecular-fluorescence complementation to study physical interactions between SMN, other proteins, and RNAs in motor neuron axons. They found proteins and RNAs are not properly localized to axons when SMN protein is low.
Jocelin Côté, a Cure SMA-funded researcher from the University of Ottawa, also addressed how the SMN protein works in motor axons, focusing on the role of two proteins called HuD and KSRP. These proteins are regulated by the presence or absence of a tag called arginine methylation. The tag determines if these proteins interact with SMN protein in motor neuron axons. Increasing the amount of HuD corrects defects in the axon due to SMN loss, suggesting stimulation of HuD could be beneficial in SMA.
Sara Custer, a Cure SMA-funded researcher from the Androphy lab at Indiana University, examined the role of SMN in transporting other proteins around cells, a process called vesicle trafficking. They discovered that the SMN protein interacts with another protein, alpha-COP, during this process. When levels of either protein are low, the process does not work properly. This results in an accumulation of autophagosomes, a cellular body that removes abnormal proteins and cellular structures. They proposed that defective trafficking of vesicles and the accumulation of autophagosomes causes chronic stress to cells, which may contribute to motor neuron pathology in SMA.
Finally, Nimrod Miller, from the Cure SMA-funded Ma lab at Northwestern University, addressed the role of mitochondrial dysfunction in SMA. Mitochondria are cellular structures that generate energy for the cell. They found defective mitochondrial movement along motor neurons axons with low SMN levels. This movement is thought to be needed to replenish mitochrondria in cells when they are old or damaged. These defects could contribute to SMA motor-neuron pathology.