Ubiquitin Pathway Activation: A New Strategy for Treating ALS
Abstract
In the past decade, we have recognized that conventional approaches to chemotherapy, support therapies, cell implantation, and related strategies fail because they do not effectively address the primary cause or underlying disease mechanism of amyotrophic lateral sclerosis (ALS). Only one drug, Riluzole, is currently approved to treat ALS and it only extends life by a few months and has a marginal effect on the quality of life. A second drug, Neudexta, is approved to treat symptoms of pseudo bulbar affect, but has no effect on the disease course. Thus, new approaches to finding treatments for ALS and related neurological disease are needed. In ALS and other neurodegenerative diseases a common feature is the disruption of quality control of protein homeostasis. This often results in the accumulation of misfolded and toxic protein aggregates that may also subvert the available resources of the neuron to implement effective protein homeostasis most crucially at the synapse. Although our understanding of the underlying pathology and genetic origins has improved in recent years, ALS remains largely untreatable and incurable. The therapeutic idea to be explored in our study is that enhancing the efficacy of the protein recycling system at specific check points with novel compounds and actions may be an approach that leads to new avenues of therapy. We have discovered a class of compounds that in preliminary studies activate one of the protein recycling pathways and thus degrade misfolded proteins from the cell. Thus, we will test small molecules for their ability to activate protein recycling pathways using some of our existing compounds as well as screening focused compound libraries for new drug candidates. We hope to find several new drug candidates which will undergo additional testing in animal models in future studies. Ultimately, we envision that activating protein recycling will be beneficial to the majority of ALS cases where protein aggregates are found and possibly in other neurodegenerative diseases.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710086
Entities
People
- Teepu Siddique
Organizations
- Northwestern University
- United States Army