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ALS Alert Newsletter

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Jun 7
2021

Packard Center's 21st annual symposium held virtually with record attendance.

Annual event welcomed 525 participants from seven countries and 115 institutions.

The Covid-19 pandemic has touched nearly every aspect of daily life, and this year’s annual Packard Center Symposium was no exception. For the first time in the Center’s 21-year history, the annual symposium was held virtually instead of in Baltimore. The lack of face-to-face contact was disappointing, says Packard director Jeff Rothstein, but the online format allowed a record-breaking 525 people to participate in the meeting.

Whether online or in Baltimore, the Packard Center’s annual symposium underscores its mission: bringing scientists together to better understand ALS and work towards a cure. Collaboration isn’t an afterthought, either; it’s built into the Center’s very structure. Scientists are required to share their progress over the past year, including both successes and setbacks, with their colleagues. Because few of these results have been peer reviewed or published, details about the findings aren’t ready to be shared. But the pandemic hasn’t slowed ALS science.

This year’s symposium featured updates on existing areas of research as well as some brand-new findings. As scientists delve more deeply into the genetic contributors to motor neuron disease, they have continued to identify more and more genes that affect risk for ALS. Although most of these mutations are extremely rare, they highlight molecular pathways in the cell that can provide insight on the development of disease in everyone with ALS regardless of the cause. These new discoveries have already begun opening new doors for the creation of new therapies and biomarkers.

As it has in previous years, however, much of the conference focused on malfunctions in both the TDP43 protein and with the C9orf72 gene. TDP43 is misfolded and mislocalized in 97% of ALS cases. Although scientists have long known that misfolded TDP43 is toxic, what is less clear is how this misfolding leads to disease. Using a variety of new techniques, including optogenetics (which uses light to control the activity of genetically engineered proteins and neurons), Packard scientists have moved closer to understanding exactly how TDP43 forms insoluble clumps, and what this means for the cell. Not only does the cell have to cope with the toxic misfolded protein, it also means that TDP43 protein isn’t available to perform its normal function as an RNA-binding protein. Tracking both of these processes will be important to understanding why TDP43 misfolding is central to ALS and other neurodegenerative conditions, and in developing therapies to target this misfolding.

Similarly, the repeat expansion in the C9orf72 gene can also contribute to disease both through a toxic gain of function (the presence of the repeat expansion leads to something harmful) and/or a loss of function (the lack of adequate amounts of normal C9orf72 protein creates problems). 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.

An emerging area of research concerns newly discovered malfunctions in the normal movement of proteins and other macromolecules between the nucleus and cytoplasm, known formally as nucleocytoplasmic transport. 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 and understanding the role of these cell types will help researchers understand how motor neurons degenerate and die. 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.

Another unique feature of Packard’s annual event was a virtual poster session, held over two nights. The session welcomed posters from 25 postdocs and graduate students. Held on an interactive platform called Spatial Chat, participants could view each poster, maneuver around the session, speak to the presenter, and ask questions. There were also several rooms organized by topic. A panel of six Packard Center senior investigators served as judges. This unique virtual format was an excellent opportunity for young investigators to present their work and get feedback. Poster session winners included:

First Place: Chen Eitan (Horanstein Lab - Weizmann Institute of Science)
Runners Up: Mor Alkaslasi/Zoe Piccus (Le Pichon Lab - NIH), Shaopen Wang (Sun Lab – Johns Hopkins University), Michael McMillan (Barmada Lab – University of Michigan)

Although this year’s symposium was unique in format, Packard scientists showed that the pandemic hadn’t stalled their quest to understand ALS. Everyone is looking forward to gathering again next year in Baltimore.