2015 SMA Researcher Meeting Summary: SMN Partners and Targets, Part 2

We will be posting a series of summaries from our 2015 researcher meeting, highlighting some of the most interesting new developments and discoveries presented there. This update covers the second half of a session on SMN Partners and Therapeutic Targets. The session was moderated by Rashmi Kothary, PhD.

SMN Partners and Candidate Therapeutic Targets, Part 2

Individuals with SMA do not correctly produce survival motor neuron (SMN) protein at high enough levels, due to a genetic mutation in the SMN1 gene. Over the preceding several years, we have become increasingly excited about the potential to restore SMN expression. This could be done by prompting the low-functioning SMN2 gene (the SMA “backup gene”) to make more protein, or by replacing SMN directly using, for example, gene therapy. Indeed, therapies targeted at restoring SMN levels are currently in clinical trials. However, there may be ways to treat SMA that do not involve increasing SMN levels. Drugs targeting alternative pathways should be able to be used in combination with SMN enhancing therapies.

Identifying alternative routes for therapies will be guided by understanding what other cellular proteins interact and work together with the SMN protein. This session focused on studies designed to find and better understand proteins that bind and work in concert with the SMN protein.

For more on the background of this session, please see our summary of part 1.

The second half of this session featured four additional talks.

First, Sara Custer from the Androphy laboratory at Indiana University presented on a novel function for SMN in neurons. She showed that SMN interacts directly with an intercellular protein called alpha-COP. This interaction was important for neuronal development. It is possible that this interaction could be exploited for therapeutic benefit once it is understood better.

Next, Christine Beattie also presented on the function of SMN in neuronal development. She focused on the interaction with another key protein in cells, called HuD. It is important for transporting of RNA from the cell body into axons and growth cones that extend out to the muscle. She continues to study the functional relevance of this interaction with SMN using the zebra fish model system for SMA.

The third talk was by Seyyed Mohsen Hosseini-Barkooie from the Wirth lab at the University of Cologne, who presented his efforts at understanding the mechanism behind the positive impact of the genetic modifier plastin-3 on the growth in SMN-depleted motor neurons. He showed that increasing the amount of plastin-3 or its interaction partner coronin-1C improved specific aspects of motor neuron axonal development and function.

Finally, Elena Bianchetti from the Pellizzoni lab at Columbia University presented on the contribution of another protein called Stasimon on the defects in the sensory-motor circuit of SMA mice. Stasimon is incorrectly produced in conditions where there are low amounts of SMN protein. Replacing back Stasimon to SMA mouse models, only improved some, but not all, aspects of the SMA defects in the mice. Therefore, she concluded that SMA pathology is caused by defects in many genes that result in conditions of low SMN levels, not just a singe gene change to Stasimon.

Overall, the work from this session highlighted the numerous cellular proteins and genes that are impacted when SMN levels are low. This suggests that SMA pathology is a complex process, and many of these can possibly be exploited for therapeutic benefit.

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