The SMA Researcher Meeting is the largest research meeting in the world specifically focused on SMA. This year we had a record setting 350 attendees. The goal of the meeting is to create open communication of early, unpublished scientific data, accelerating the pace of research. The meeting also furthers research by building productive collaborations—including cross-disciplinary dialogue, partnerships, integration of new researchers and drug companies, and educational opportunities for junior researchers.

We will be posting a series of summaries from our 2016 researcher meeting, highlighting some of the most interesting new developments and discoveries presented there. This update covers the first of two sessions on therapeutic targets. Research has revealed that a number of systems, pathways and processes are affected in SMA. The presenters in these two sessions are investigating these different aspects of SMA, looking for new ways to treat SMA that target other areas. Ultimately, these approaches could be used in combination with approaches that address the underlying genetics of SMA, giving us the best chance of a comprehensive, effective treatment. This is particularly important as we seek to develop treatments for all ages, stages and types of SMA.

The session was moderated by Cure SMA Scientific Advisory Board Member Sam Pfaff, PhD.

Nimrod Miller from the Ma laboratory at Northwestern University described his research on mitochondrial function in SMA. In order to keep motor neurons healthy, high energy demands must be met. Mitochondria are the cellular factories that produce the energy needed to help meet this demand. Investigating if mitochondria are properly functioning in SMA, when SMN levels are low, lends insight into why SMA motor neurons die.

To that end, Miller looked at purified motor neurons from SMA mice and discovered a change consistent with energy metabolism defects. When he looked inside the motor neurons, he found that, the difference in electric potential between the inside and the outside of the cells and the movement of the mitochondria inside the cells were abnormal. His findings raise the possibility that SMN is required to maintain healthy mitochondria, thereby revealing a possible new target for therapy.

The next talks focused on how SMN interacts with other molecules in the cell. In order to make the necessary proteins for survival, the cell must contain a code for each of the proteins it needs. We call this code DNA. But before the cell makes DNA, it makes a very important precursor molecule called RNA. The cell has numerous way to modify the steps of this process in order to change gene expression, and we may be able to treat SMA by finding ways to impact this process at key points. For example, RNA-binding proteins, as the name implies, bind to RNA. In doing so, they impact the function of RNA.

Paul Donlin-Asp from the Rosssoll lab at Emory University described his work on the role of SMN in transporting RNAs. He was able to monitor the cobinding of a RNA binding protein, IMP1 (ZBP1), with SMN protein and its interacting partners. His studies indicate that IMP1 binding to RNA is reduced in rodent and human cells with mutations that reduce SMN protein levels. This provides direct evidence that SMN broadly functions as a chaperone for interaction between proteins and RNA and suggests a broad spectrum of RNA processing defects contribute to SMA.

Christine Beattie (Ohio State University) presented her work showing that SMN forms complexes with RNA-binding proteins (RBPs) in motor neurons during development. These SMN-RBP complexes are ever changing during the developmental period, suggesting that they bind unique RNAs during different developmental phases. Zebrafish with mutations in these RBPs present very similarly to fish with low SMN levels. This suggests that these RBPs are affecting the same key developmental events as SMN. Further work is being done to identify the RNAs bound by the SMN-RBP complexes. Once the RNAs are identified, the team will determine if they are abnormal in SMA and how that impacts motor neuron development.

Chia-Yen Wu in the Kalb laboratory at Children’s Hospital of Philadelphia used C. elegans (worms) as a model to test whether perturbing the longevity pathways that are well defined in this organism can extend the life of worms lacking SMN. She showed that attenuation of the daf-2/IGF1R pathway improves lifespan and locomotor activity in SMN mutant C. elegans.

Likewise, Patrick O’Hearn from the Hart laboratory at Brown University described work investigating microRNA, small RNAs that function to regulate gene expression, regulators that are dependent upon SMN using C. elegans. He examined Gemin3 function because this Gemin 3 is a protein that interacts with SMN and is a putative component of the machinery that helps make microRNAs. He found that SMN is required to express high levels of Gemin3, and then examined a particular microRNA, Mir2, as a possible target. His work suggested that Mir2 is a negative regulator of GAR2 (a muscarinic acetylcholine receptor important for neurons). His findings indicate that over-active neurotransmission may occur in SMA neurons.