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Apr 27

Researchers share results, ideas at 16th Annual Packard Symposium

Annual Symposium was attended by 180 scientists from more than 50 institutions.

This past March, more than 180 ALS scientists gathered at the Baltimore Hyatt Regency for the 16th annual Packard symposium. The goal of this gathering, as with the fifteen previous symposia, is to convene grantees from the Packard Center and elsewhere in the ALS community to discuss the latest ALS research. By openly sharing results, scientists can make discoveries more quickly and translate them into potential therapeutics more efficiently.

Packard Center Science Director Piera Pasinelli and NEALS co-chair Jonathan Glass.

One of the newest scientific initiatives, Answer ALS, was introduced by Packard Director Jeff Rothstein. The goal of the program is to obtain biological samples from 1000 individuals with ALS and then deeply characterize those samples using every type of -omics technology, including genomics, epigenomics, proteomics, metabolomics, and more. Individuals will also be monitored clinically and will donate brain and spinal cord samples postmortem. By capturing the broad spectrum of ALS illnesses and working to understand the many different facets of this illness, researchers hope one day to target different drugs to different patients, as well as generating a deeper knowledge of the various cellular pathways that contribute to disease. All of the data obtained will be openly shared, and the discoveries made as a result of these samples will be freely shared with the general public.

As in previous years, researchers presented work related to genes known to contribute to ALS, such as SOD1, TDP43 and C9orf72. What appears to be emerging from the study of all of these different mutations is the links between RNA metabolism, protein quality control, and ALS. Autophagy, the process by which cells break down and recycle old and misfolded proteins, plays a major role in protein quality control, and received attention by several scientists. Increasing the cell’s ability to break down misfolded TDP43 proteins, which can build up and form toxic clumps in motor neurons, may help slow the progression of ALS, and researchers have begun to investigate several ways to potentially make this happen. They have also been investigating how this process helps with motor neuron survival, as a way of validating any therapies.

University of Massachusetts researcher Zuoshang Xu.

Other scientists are looking to decrease TDP43 levels through means other than autophagy, such as through the creation of antibodies targeting the protein that will prevent it from leaving the nucleus, where it’s required to do its job, and forming aggregates in the cytoplasm. New animal models of TDP43-linked ALS are also helping scientists investigate these processes and identify other genes and proteins that may help alter the toxicity of TDP43 protein aggregates.

The importance of the C9orf72 mutation in understanding ALS is also reflected in the amount of research being performed on this repeat expansion. The discovery that the repeat expansion led to the synthesis of small proteins made up of two amino acids (known as dipeptide repeat proteins, DPRs) that are toxic to cells has led Packard scientists to investigate this phenomenon more deeply. Several C9orf72 animal models have been created recently, which are allowing investigators to study the pathogenic cascade of events that leads to motor neuron degeneration and death, as well as genes that could modify the toxicity of the repeat expansion.

Packard advisors Harry Orr and Maury Swanson.

DPRs, however, aren’t the only potential source of toxicity from C9orf72. RNA foci have also been identified in C9orf72 patient cells and in animal models, but the role of these foci in the disease process remains unclear. Other researchers have focused on C9orf72-related defects in the transport of molecules between the nucleus and the cytoplasm. Recent work has shown that this transport is impaired, but precisely how it’s impaired and how these transport defects contribute to disease hasn’t yet been elucidated. In order to test therapies to potentially reverse C9orf72-related toxicity, researchers need biomarkers, which still need to be identified. Scientists also continue to work to understand what the gene actually does, and the potential effects if the gene is not transcribed and translated properly.

Answer ALS investigator Leslie Thompson.

SOD1 might have been the first ALS-linked gene mutation to be discovered, but research remains ongoing as to its contributions to disease. Mutations in this protein appear to affect cellular metabolism in patient cells and in mouse models. These metabolic changes appear to play some role in disease, and they may help explain some baffling cellular findings. Scientists have also begun to understand the temporal cascade of selective cell damage that is done by mutant SOD1. The prion-like nature of mutant SOD1 may also help potentially explain how ALS pathology spreads from cell to cell.

New gene mutations are continually being linked to ALS, and awareness of the contributions of these proteins to the disease process is providing important clues about what causes ALS and how it might be treated. Other proteins, such as FUS, Profilin-1, UBQLN2, Connexin 43, and GDE2, are also being characterized and their role in the onset or progression of disease being teased apart. This work is providing a richer, more nuanced picture of what precisely goes wrong in ALS. Senataxin is a DNA/RNA helicase, important for separating the two strands of the double helix and allowing transcription and translation to take place. Mutations in this protein have been linked to both familial and sporadic ALS. Ataxin-2 has been linked to both spinocerebellar ataxia and ALS, and is required for the formation of stress granules, which have also been linked to ALS. Work presented on stress granules continues to emphasize the importance of these jumbles of RNA and protein in ALS. Ways to coax these stress granules to break down and help the cell return to normal functioning are being investigated as potential therapeutics for ALS.

Hristelina Ilieva and Packard Center Director Jeff Rothstein.

NEALS, the NorthEast ALS Consortium, continues to help link basic science discoveries into ALS clinical trials. They currently have 35 studies, 24 of which are ongoing, 16 are completed, and two are in the start-up phase. Researchers presented on results from several clinical trials, including those for the anti-malarial drug pyrimethamine and the anti-seizure medication retigabine. Scientists are also investigating the clinical relationship between slow vital capacity and ALS functional decline, which may help provide better insights into clinical trial results.