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Apr 14

Packard Center's Annual Symposium Celebrates 20 Years of Collaboration

Annual meeting welcomes 300 researchers to Baltimore.

For the twentieth year in a row, grantees and guests of the Robert Packard Center for ALS Research gathered in Baltimore’s Inner Harbor to share the results of the previous year’s research. The annual symposium is more than a mere highlight of findings and progress. It encompasses the raison d’être of the Center: how collaboration will be the key to understanding ALS and, perhaps one day, finding a cure. Without this spirit of openness and a willingness to share data, scientists would be left competing with each other instead of working together towards a common goal. To facilitate this openness, the details of the scientific findings are kept confidential until they have been vetted and published in peer-reviewed journals.

The topics at this year’s symposium combined perennial discussions about such factors as the role of the TDP43 protein and the functions and dysfunctions of stress granules (tangles of RNA and protein that form when the cell is stressed and then dissolve afterwards), as well as newer topics such as the movement of molecules between the nucleus and cytoplasm (aka nucleocytoplasmic transport) and advanced analyses of ALS pathology at the single cell level.

As has been the case since it was discovered in October 2011, a large portion of the research presented at the symposium focused on the C9orf72 repeat expansion, the most common genetic cause of ALS. In the previous year, Packard scientists have made progress in understanding how this repeat expansion leads to disease. Ongoing work presented at the symposium have continued investigations into how the repeat expansion creates toxic proteins called dipeptide repeats (DPRs). Researchers noted parallels between DPRs produced by the C9orf72 repeat expansion and those formed by similar mutations in other diseases, such as Huntington’s. They also examined the process of how the DPRs are synthesized in the cell, going from DNA to RNA to protein. Understanding the details in these processes could provide useful targets for the development of ALS therapies.

TDP43, which is misfolded in 97% of ALS cases, even sporadic disease, also remains a focus of Packard scientists. They have spent the last year trying to understand the molecular mechanisms that lead to this misfolding and the incorporation of TDP43 into stress granules. Although scientists have long known that misfolded TDP43 is toxic, what is less clear is how this misfolding leads to disease. Researchers expanded upon previously published work showing the regions of the protein responsible for misfolding and how mutations could increase or decrease the probability of aggregation. They also examined links between TDP43 and impaired nucleocytoplasmic transport.

These transport defects have been linked not just to TDP43 but also to the C9orf72 repeat expansion. Scientists have been hard at work trying to understand the intricate relationships between protein misfolding and the large, complex proteins of the nuclear pore. Research is ongoing to determine which of the nuclear pore proteins may enhance or inhibit the misfolding of proteins like TDP43 and which are affected by the C9orf72 repeat expansion. Packard grantees are also trying to parse out the order of events and how nucleocytoplasmic transport problems emerge from misfolded proteins or vice versa.

As much as motor neurons are the focus of pathology in ALS, other types of cells are involved. Other neural cells such as astrocytes and microglia are also known to play a role in the development of disease. Small hemichannels made up of six connexin proteins allow ions and small molecules to pass between cells via a gap junction. Motor neurons and astrocytes are connected via hemichannels, and scientists are currently investigating if this may allow ALS pathology to spread from neuron to neuron. Researchers are also studying the connection between motor neurons and muscles at the neuromuscular junction (NMJ). As motor neurons degenerate, they lose their connections to muscles at the NMJ. Previous studies revealed that the body’s ability to repair the NMJ is impaired in ALS, so Packard scientists have begun trying to find ways to improve healing, which they hope may also improve movement and other vital functions such as breathing and swallowing.

Representatives from other ALS organizations, such as Answer ALS and NEALS, also presented their results at the symposium. NEALS shared the status of some of their clinical trials as well as discussing the new HEALEY ALS Platform Trial, which is testing three different drugs simultaneously. The trial is pooling controls from the three groups so that more patients have the opportunity to get a novel treatment. Answer ALS has completed much of the trial’s clinical phase and now has shifted into analyzing the volumes of data obtained from each patient. The group is using this detailed information to identify potential subgroups of ALS patients and target therapies towards those most likely to benefit.

This year’s keynote speaker was Bob Brown, a neurologist at the University of Massachusetts Medical School and a leader in the field of ALS research. His lab discovered the first genetic mutation linked to ALS in the gene SOD1 in 1994. Since then, the number of ALS-linked genes has grown dramatically, and Brown shared his perspective on watching the field bloom. Brown also discussed some of the targeted ALS therapies currently in development, especially antisense oligonucleotides (ASOs) currently in trials for individuals with ALS caused by mutations in SOD1 and C9orf72.

Researchers are planning to return to Baltimore next year for another symposium where they will once again share their findings and even their failures on their quest for an ALS cure.

  • Jeff Rothstein, Packard Center founder and director, recognizes Piera Pasinell, Packard Center's former science director at the start of the annual meeting.

  • Don Cleveland from the University of California San Diego was the event's first speaker.

  • Mondira Kundu from St. Judes Children’s Research Hospital presented on the role of the autophagy-including kinases ULK1/2 in the disassemby of stress granules.

  • Ben Zaepfel, a graduate student at Johns Hopkins University, poses a question.

  • Michael Ward from the National Institute of Health presented on the molecular convergence in ALS/FTD.