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01.03.2018

One step further towards potential therapeutics for ALS

Sterneckert group © CRTD

iPSC-derived neurons © Lara Marrone (Sterneckert group)

Amyotrophic Lateral Sclerosis (ALS) is a lethal disease of the central and peripheral nervous system characterized by muscle stiffness followed by progressive weakening and paralysis due to the death of motor neurons.

"FUS" (short for Fused in Sarcoma) is a nuclear protein that exerts a plethora of crucial biological functions. Certain ALS mutations cause FUS to become aberrantly localized to the cytoplasm. As a result of this mistaken localization, FUS is recruited to structures that form within cells upon stress called "stress granules". These aberrant stress granules can lead to the formation of FUS protein aggregates, increased cellular stress, and, as a consequence, neuronal death.

Compounds that prevent the formation of aberrant FUS-containing stress granules could be effective drugs for ALS patients. However, stress granules have been very difficult to study because they lack a membrane. Jared Sterneckert, PhD, in collaboration with the research groups of Tony Hyman (MPI-CBG), Simon Alberti (MPI-CBG) and Andreas Hermann (Universitätsklinikum Carl Gustav Carus Dresden) successfully engineered induced pluripotent stem cells (iPSCs) to carry a fluorescent protein fused to FUS that enabled the analysis of aberrant stress granules in real time. This powerful technology was used to complete a screening campaign that identified compounds able to rescue stress granules in iPSCs as well as iPSC-derived motor neurons.

The team also showed that these drugs protected against neurodegeneration. In cooperation with the group of Prof. Udai Pandey (University of Pittsburgh), their promising in vitro results were corroborated in a fruit fly model. Currently, they plan on moving towards validation in mammals.

With their screening, the Sterneckert group pinpointed a class of compounds that clear out aberrant aggregation-prone proteins and could be suggested as potential therapeutics for ALS. "We found that a number of anti-depressants and anti-psychotics, which are suggested to stimulate autophagy, ameliorate pathology. The identified drugs are brain penetrant and their effects well characterized. Therefore, repurposing these drugs for ALS treatment should not be problematic, and could represent an efficacious way of slowing down disease progression in a combinatorial therapy alongside with currently available drugs", explains Lara Marrone, first author of the Stem Cell Reports paper. "We are positioned to select the most promising compounds for in vivo validation, and because we have found drugs that are clinically tested, these results could potentially be translated into clinical trials very quickly. These results again emphasize that Dresden has a great potential for important scientific findings, thanks to the advanced technologies and tight collaborations that researchers can rely on", she adds.

DOI: dx.doi.org/10.1016/j.stemcr.2017.12.018

Paper: www.cell.com/stem-cell-reports/fulltext/S2213-6711(17)30566-0