Targeting ALS-FUS Aggregation with Proteasome Inhibitors
Abstract
Here we propose to examine a specific class of molecules, proteasome inhibitors, as potential disease-modifying therapy for ALS-FUS. The vast majority of the known ALS drivers have been shown to generate intracellular structures called aggregates, that accumulate in affected neurons and lead to their degeneration. Moreover, it is well known that many of the ALS drivers co-aggregate in different ALS subtypes, including ALS-C9orf72 and ALS-TDP-43; however, FUS-ALS forms distinct aggregates that do not sequester other major ALS drivers, and vice-versa. These observations suggest that the molecular properties of the ALS driver FUS, as well as the molecular properties of FUS, aggregates in the disease, are different than those of other ALS drivers. This notion calls for therapeutic strategies that are specific for ALS-FUS. Using a highly quantitative molecular readout for mutant FUS aggregation in cell models, the Shalgi lab has found that, in sharp contrast to other ALS drivers, as well as to other neurogenerative disease aggregating proteins, treatment with a class of small molecule drugs, namely proteasome inhibitors, leads to a marked reduction in the aggregation of FUS harboring ALS-associated mutations. This class of molecules is known to primarily inhibit the process of protein degradation in cells. Accordingly, the current dogma in the field stated that treatment with proteasome inhibitors should in fact enhance aggregation, rather than inhibit their formation. Nevertheless, in contrast to the dogma in the field, and to other aggregating proteins, our observations of reduced mutant FUS aggregation following proteasome inhibitor treatment recapitulated for a number of different types of these molecules. Thus, in the current project, we propose to take these initial observations to the next level, and to establish the potential of proteasome inhibitors as specific disease-modifying therapy for ALS-FUS, with the ultimate goal of preventing FUS aggregation, and thereby slowing down disease progression. Importantly, one of the strengths of the proposed study is that it will focus both on efficacy studies, in model systems and in animal models, as well as on unraveling the mechanism underlying this specific aggregation prevention effect on mutant FUS, examining a variety of mutations. Thus, a successful outcome of this study bears great therapeutic potential, as it will offer a proof of concept for efficacy as well as mechanism-driven therapy. While the current study is aimed at examining various sub-classes of proteasome inhibitors in neuronal models and in animal models of ALS-FUS, several derivatives have been shown to cross the blood-brain barrier and effectively penetrate into neurons. Importantly, some of these derivatives are currently in phase-III clinical trials for other diseases. Therefore, a successful outcome of the proposed research will pave the way for potential drug repurposing, thereby providing a relatively faster track for moving forward into the clinic, in order to offer a therapeutic avenue for patients with ALS-FUS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310319
Entities
People
- Reut Shalgi
Organizations
- United States Army