Screening Therapeutic Agents Targeting Neuromuscular Junctions in ALS
Abstract
Amyotrophic lateral sclerosis (ALS), or Lou Gehrig s disease, is a late-onset fatal neurodegenerative disorder characterized by progressive loss of the nerve cells of the brain and spinal cord responsible for the control of muscle movements (called motor neurons). Patients suffering from ALS have a 2- to 5-year average life expectancy after diagnosis with a progressive impaired capacity to walk, swallow, talk, and breathe. Most ALS cases (~90%) have an unknown cause and are referred to as sporadic. However, 10% of cases are inherited, with the most common mutations being found in genes producing superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), and C9ORF72. To date, there is no cure or effective treatment to significantly slow disease onset and progression. Hence, there is an urgent need for effective therapeutics. One of the earliest events in ALS is loss of the connections between motor neurons and muscles, which are critical for our most basic motor functions, such as breathing. The disruption of this connection leads to the destruction of sophisticated structures called neuromuscular junctions (NMJs), the contacts that transfer the motor neuron commands onto the muscles. Importantly, the preservation of the motor neurons is not sufficient to prevent the loss of the NMJs, thus pointing to NMJs as potential sites of toxicity. Therefore, targeting NMJs represents an unexplored therapeutic strategy to treat ALS. This project represents a synergistic collaboration between two academic investigators proposing an innovative strategy that combines structural and functional analyses of NMJs in multiple mouse and human in-vitro and in-vivo models for muscle denervation induced by ALS-causing mutations (SOD1, TDP-43, and C9orf72). We propose to identify small molecules that prevent the disconnection or stimulate (re)connection between motor neurons and muscles in ALS. We have assembled a comprehensive set of approaches that will allow us to rapidly screen a large number of drugs to identify those that can help maintain NMJ structure and functions. The power of our approach is to then use models that recapitulate the disease at NMJs to more stringently select the most efficient drugs. These models include genetic mouse and human models, including ones from sporadic forms of ALS. This approach, if successful, may identify one or more drugs with the potential to be repurposed for the treatment of ALS. The system can also be used more broadly for identifying completely new drugs that can encourage maintenance of nerve attachment to muscle or stimulate its reattachment. Recognizing that NMJ loss is an early hallmark of disease and that efforts targeting the initial step - muscle denervation - are scarce, our multi-pronged approach has the potential to uncover new insights into the unknown mechanisms underlying toxicity at the NMJs and establish the preclinical proof of concept for targeting NMJs as a therapy for ALS patients. Thus, our findings are likely to be widely applicable to most ALS forms, including sporadic cases, and have the potential to be directly translated into effective therapeutics that may delay muscle denervation and improve patients autonomy and quality of life.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910135
Entities
People
- Sandrine Da Cruz
Organizations
- Ludwig Institute for Cancer Research
- United States Army